Erlotinib hydrochloride CAS 183319-69-9
Introduction：Basic information about Erlotinib hydrochloride CAS 183319-69-9, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Erlotinib hydrochloride Basic informationIndications and Usage Mechanisms of Action Clinical Research
| Product Name: | Erlotinib hydrochloride |
| Synonyms: | ERLOTINIB HCL;ERLOTINIB HCL SALT;ERLOTINIB HCL SALT :TARCEVA;Erlotinib, Hydrochloride Salt;N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, Hydrochloride Salt, OSI 774, Tarceva;N-(3-Ethynylphenyl)-6,7-bis-(2-methoxyethoxy)-quinazolin-4-amine;[6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4yl]-(3-ethynyl-phenyl)-amine;Tarceva HydrochlorideSee E625000 |
| CAS: | 183319-69-9 |
| MF: | C22H24ClN3O4 |
| MW: | 429.9 |
| EINECS: | 620-491-0 |
| Product Categories: | Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Heterocyclic Compounds;anti-neoplastic;Anti-cancer&immunity;Antineoplastic;Tarceva;Inhibitors;Molecular Targeted Antineoplastic;API;183319-69-9 |
| Mol File: | 183319-69-9.mol |
Erlotinib hydrochloride Chemical Properties
| Melting point | 223-225°C |
| storage temp. | Inert atmosphere,Store in freezer, under -20°C |
| solubility | Soluble in DMSO (up to 18 mg/ml with warming). |
| pka | pKa (25°): 5.42 |
| form | Yellow powder. |
| color | White or off-white |
| Stability: | Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months. |
| InChI | InChI=1S/C22H23N3O4.ClH/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22;/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25);1H |
| InChIKey | GTTBEUCJPZQMDZ-UHFFFAOYSA-N |
| SMILES | C12C=C(OCCOC)C(OCCOC)=CC=1N=CN=C2NC1=CC=CC(=C1)C#C.Cl |
| CAS DataBase Reference | 183319-69-9(CAS DataBase Reference) |
Safety Information
| Safety Statements | 24/25 |
| WGK Germany | WGK 3 |
| RTECS | VA0971200 |
| HS Code | 29335990 |
| Storage Class | 11 - Combustible Solids |
| Hazard Classifications | Acute Tox. 4 Oral |
| Indications and Usage | Erlotinib hydrochlorate is a small molecule tyrosine kinase inhibitor which acts reversibly on epidermal growth factor receptors, a hydrochloride of erlotinib, a molecular-targeted drug. The US Food and Drug Administration (FDA) has approved erlotinib (Tarceva) combined with gemcitabine as a first-line treatment for locally advanced and metastatic pancreatic cancer. It is mainly used as a second- or third-line treatment for locally advanced or metstatic non-small cell lung cancer (NSCLC) and as a treatment for pancreatic cancer. It is used as a tyrosine inhibitor for NSCLC treatment. |
| Mechanisms of Action | The small molecular compound erlotinib is a tyrosine kinase receptor inhibitor which inhibits the proliferation of tumor cells by inhibiting phosphorylation, binding to the intracellular catalytic domain of tyrosine kinase in competition with ATP, thus blocking downstream signal transduction and inhibiting activity of tumor cell ligand dependent HER-1/EGFR. |
| Clinical Research | Phase I clinical trials showed that the main toxicities and side effects of erlotinib were dose-dependent rashes and diarrhea. Other rare side effects included headaches, nausea, and vomiting. Phase II trials used erlotinib as a second-line anticancer drug, with efficacy matching second-line chemotherapy drug docetaxel. Phase III randomized control trials (BR21) mainly focused on NSCLC patients (locally advanced and distant metastasis) after the failure of first- or second-line chemotherapy. The treatment group, with 488 cases in total, took 150mg of erlotinib daily. The control group (243 cases) took a placebo. The study showed: Median survival rate: 6.7 months for the treatment group, 4.7 months for the control (P<0.001, hazard ratio HR=0.73) 1 year survival rate: 31.2% for the treatment group, 21.5% for the control Median time of no progression: 9.9 weeks for the treatment group, 7.9 weeks for the control Meanwhile, symptomatic improvement in the treatment group was more pronounced. Based on the results of the BR21 study, several further phase III clinical trials were conducted. The TRIBUTE trial combined erlotinib with chemotherapy. The treatment group used chemotherapy (carboplatin + paclitaxel) + erlotinib, while the control used the same chemotherapy alone, with a total of 1,059 late-stage NSCLC patients. The effectiveness of the treatment group was 21.5%, and the control group 19.3%; median survival times were 10.8 and 10.6 months, respectively, and the times of tumor progression (TTP) were 5.1 and 5.0 months. Meanwhile, TALENT trials, with 1,172 NSCLC patients, also investigated the effects of adding erlotinib to chemotherapy (gemcitabine + cisplatin), and also failed to show that erlotinib significantly increased its effects. |
| Description | Erlotinib, launched as once daily oral treatment for patients withnon-small-cell lung cancer (NSCLC), is an inhibitor of the epidermal growth factorreceptor (EGFR) tyrosine kinase, and it is the second small-molecule drug tobe marketed with this mechanism of action. Both erlotinib and its predecessor,gefitinib, are members of the anilinoquinazoline class of tyrosine kinase inhibitors.They compete with the binding of ATP to the intracellular tyrosine kinase domainof EGFR, thereby inhibiting receptor autophosphorylation and blocking downstreamsignal transduction. Erlotinib is prepared by the condensation of 3-ethynylanilinewith 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline, which is a keyintermediate obtained in five synthetic steps starting from ethyl 3,4-dihydroxybenzoate. In vitro, Erlotinib inhibits purified human EGFR tyrosinekinase with an IC50 of 2 nM and blocks EGFR autophosphorylation in cellularassays with an IC50 of 20nM. Treatment of human colon cancer cells with erlotinibwas associated with growth inhibition, G1 cell cycle arrest, and apoptosis.Oral administration of erlotinib in athymic mice produced potent antitumor effectswith an ED50 of 9.2 mg/kg/day for HN5 head and neck xenografts and 14 mg/kg/day for A431 epidermoid xenografts. The absorption of Erlotinib following oraldosing is approximately 60%. Food greatly enhances the absorption allowing foralmost 100% bioavailability of the dose. The time to reach peak plasma levels of the drug is about 4 hours, and the half-life is approximately 36 hours. Steady-state druglevels are reached in 7 to 8 days. Erlotinib has high protein binding (93%) and hasan apparent volume of distribution of 232 L. It is metabolized primarily byCYP3A4 and to a lesser extent by CYP1A2 and CYP1A1. The drug is mainlyexcreted in the feces with less than 9% of the dose found in the urine. Erlotinib islabeled for the treatment of patients with locally advanced or metastatic NSCLCwho have failed one or more previous chemotherapy regimens. The recommendeddosage is 150 mg daily until disease progression is detected. In a randomized, doubleblind, placebo-controlled trial involving 731 patients, 150 mg/day oral dose oferlotinib resulted in a median overall survival of 6.7 months compared with 4.7months in the placebo group (p＜0.001). Progression-free survival was 9.9 weeksand 7.9 weeks in the erlotinib and placebo groups, respectively (p＜0.001). Survivalat one year was 31.2% in the erlotinib group versus 21.5% in the placebo group.The use of erlotinib showed greater benefit in patients with EGFR positive tumorsand in those who never smoked. The most common adverse events reported inclinical trials were rash (9%) and diarrhea (6%). Elevations in liver functiontests were also seen; however, these effects were mainly transient or associated withliver metastases. As previously noted for gefitinib, erlotinib is also shown tolack any clinical benefit in concurrent administration with platinum-based chemotherapy. |
| Chemical Properties | Off-White Solid |
| Originator | Pfizer (US) |
| Uses | Selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. Antineoplastic |
| Uses | Erlotinib HCl (OSI-744) is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl. Phase 3. |
| Uses | Erlotinib hydrochloride (V), a quinazoline derived smallmolecule inhibitor of epidermal growth factor receptor(EDGFR) tyrosine kinase, was approved in November,2004, for the treatment of advanced or metastatic non-smallcelllung cancer. It belongs to the same class as gefitinib,another quinazoline approved for treatment of advanced lungcancer, but with improved pharmacokinetic properties. The molecule was originated by Pfizer and developmentinitiated in collaboration with OSI, which assumed fullrights to the drug when Pfizer merged with Warner Lambert.Subsequently, Genentech/Roche went into licensingagreement with OSI to develop and market the drug in theUS and Worldwide. |
| Definition | ChEBI: A quinazoline hydrochloride compound having a (3-ethynylphenyl)amino group at the 4-position and two 2-methoxyethoxy groups at the 6- and 7-positions. |
| Brand name | Tarceva(OSI). |
| General Description | Erlotinib is available as 25-, 100-, and 150-mg tablets fororal administration and is used after failure of first-linetherapy in metastatic NSCLC and as first-line therapy incombination with gemcitabine in the treatment of metastaticpancreatic cancer, and in treating malignant gliomas.The structural similarity to gefitnib imparts similar pharmacokineticbehavior with bioavailability of 60% and proteinbinding of 93%. The agent is extensively metabolizedprimarily by CYP3A4. Three major metabolic pathwayshave been identified, involving oxidative-O-demethylationof the side chains followed by further oxidation to give thecarboxlic acids, oxidation of the acetylene functionalityto give a carboxylic acid, and aromatic hydroxylation ofthe phenyl ring para to the electron-donating nitrogen. Themetabolites are primarily eliminated in the feces, and theterminal half-life is 36 hours.The major toxicities seenwith the agent are dose-limiting skin rash and diarrhea.Other common adverse effects include shortness of breath,fatigue, and nausea. |
| Synthesis | The synthesis of this agent isbased on the original patent and is shown in the Scheme. The 3,4-dihydroxy benzoate 31 was reacted withbromoethyl methyl ether in the presence of potassiumcarbonate and tetrabutyl ammonium iodide to give 32 in93% yield. Nitration followed by hydrogenation provided 34in 88% yield, which was then cyclized in formamide withammonium formate to provide quinazolone 35. Subsequentreaction with oxalyl chloride gave quinazoline chloride 36,which was then reacted with 3-ethynyl aniline (37) inisopropanol in the presence of pyridine to give the desiredproduct erlotinib, which was isolated as the HCl salt (V).An alternate synthesis, that used protected 3-trimethylsilylethynyl aniline to couple to the quinazoline chloride 36, hasalso been published. |
| target | HER1/EGFR |
| storage | Store at -20°C |
| References | [1] J D MOYER. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase.[J]. Cancer research, 1997, 57 21: 4838-4848. [2] ZHE LI. Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth.[J]. The Journal of Biological Chemistry, 2007, 282 6: 3428-3432. DOI:10.1074/jbc.c600277200 [3] EDGAR R WOOD. 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.[J]. Cancer research, 2004, 64 18: 6652-6659. DOI:10.1158/0008-5472.can-04-1168 [4] G. GREVE. The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells[J]. BMC Cancer, 2015, 15 1. DOI:10.1186/s12885-015-1967-5 [5] JOAN MINGUET Peter B Katherine H Smith. Targeted therapies for treatment of non-small cell lung cancer—Recent advances and future perspectives[J]. International Journal of Cancer, 2015, 138 11: 2549-2561. DOI:10.1002/ijc.29915 |
Erlotinib hydrochloride Preparation Products And Raw materials
| Preparation Products | Erlotinib |
