183319-69-9 Usage
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 with
non-small-cell lung cancer (NSCLC), is an inhibitor of the epidermal growth factor
receptor (EGFR) tyrosine kinase, and it is the second small-molecule drug to
be 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 domain
of EGFR, thereby inhibiting receptor autophosphorylation and blocking downstream
signal transduction. Erlotinib is prepared by the condensation of 3-ethynylaniline
with 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline, which is a key
intermediate obtained in five synthetic steps starting from ethyl 3,4-
dihydroxybenzoate. In vitro, Erlotinib inhibits purified human EGFR tyrosine
kinase with an IC50 of 2 nM and blocks EGFR autophosphorylation in cellular
assays with an IC50 of 20nM. Treatment of human colon cancer cells with erlotinib
was associated with growth inhibition, G1 cell cycle arrest, and apoptosis.
Oral administration of erlotinib in athymic mice produced potent antitumor effects
with 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 oral
dosing is approximately 60%. Food greatly enhances the absorption allowing for
almost 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 drug
levels are reached in 7 to 8 days. Erlotinib has high protein binding (93%) and has
an apparent volume of distribution of 232 L. It is metabolized primarily by
CYP3A4 and to a lesser extent by CYP1A2 and CYP1A1. The drug is mainly
excreted in the feces with less than 9% of the dose found in the urine. Erlotinib is
labeled for the treatment of patients with locally advanced or metastatic NSCLC
who have failed one or more previous chemotherapy regimens. The recommended
dosage is 150 mg daily until disease progression is detected. In a randomized, double
blind, placebo-controlled trial involving 731 patients, 150 mg/day oral dose of
erlotinib resulted in a median overall survival of 6.7 months compared with 4.7
months in the placebo group (p＜0.001). Progression-free survival was 9.9 weeks
and 7.9 weeks in the erlotinib and placebo groups, respectively (p＜0.001). Survival
at 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 tumors
and in those who never smoked. The most common adverse events reported in
clinical trials were rash (9%) and diarrhea (6%). Elevations in liver function
tests were also seen; however, these effects were mainly transient or associated with
liver metastases. As previously noted for gefitinib, erlotinib is also shown to
lack any clinical benefit in concurrent administration with platinum-based chemotherapy.
Chemical Properties
Off-White Solid
Originator
Pfizer (US)
Uses
Different sources of media describe the Uses of 183319-69-9 differently. You can refer to the following data:
1. Erlotinib hydrochloride (V), a quinazoline derived small
molecule inhibitor of epidermal growth factor receptor
(EDGFR) tyrosine kinase, was approved in November,
2004, for the treatment of advanced or metastatic non-smallcell
lung cancer. It belongs to the same class as gefitinib,another quinazoline approved for treatment of advanced lung
cancer, but with improved pharmacokinetic properties. The molecule was originated by Pfizer and development
initiated in collaboration with OSI, which assumed full
rights to the drug when Pfizer merged with Warner Lambert.
Subsequently, Genentech/Roche went into licensing
agreement with OSI to develop and market the drug in the
US and Worldwide.
2. Selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. Antineoplastic
3. Erlotinib HCl is an HER1/EGFR inhibitor with IC50 of 2 nM.
4. 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.
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 is
based on the original patent and is shown in the Scheme. The 3,4-dihydroxy benzoate 31 was reacted with
bromoethyl methyl ether in the presence of potassium
carbonate and tetrabutyl ammonium iodide to give 32 in
93% yield. Nitration followed by hydrogenation provided 34
in 88% yield, which was then cyclized in formamide with
ammonium formate to provide quinazolone 35. Subsequent
reaction with oxalyl chloride gave quinazoline chloride 36,
which was then reacted with 3-ethynyl aniline (37) in
isopropanol in the presence of pyridine to give the desired
product erlotinib, which was isolated as the HCl salt (V).
An alternate synthesis, that used protected 3-trimethylsilyl
ethynyl aniline to couple to the quinazoline chloride 36, has
also been published.
References
1) Moyer et al. (1997), Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor tyrosine kinases; Cancer Res., 57 4838
2) Li et al. (2007), Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth; J. Biol. Chem., 282 3428
3) 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
4) Greve et al. (2015), The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and –wildtype non-small cell lung cancer cells; BMC Cancer, 15 947
5) Minquet et al. (2016), Targeted therapies for treatment of non-small cell lung cancer-Recent advances and future perspectives; Int. J. Cancer, 138 2549
Check Digit Verification of cas no
The CAS Registry Mumber 183319-69-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,8,3,3,1 and 9 respectively; the second part has 2 digits, 6 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 183319-69:
(8*1)+(7*8)+(6*3)+(5*3)+(4*1)+(3*9)+(2*6)+(1*9)=149
149 % 10 = 9
So 183319-69-9 is a valid CAS Registry Number.
InChI:InChI=1/C22H23N3O4.ClH/c1-4-16-5-7-17(8-6-16)25-22-18-13-20(28-11-9-26-2)21(29-12-10-27-3)14-19(18)23-15-24-22;/h1,5-8,13-15H,9-12H2,2-3H3,(H,23,24,25);1H
183319-69-9Relevant articles and documents
Convergent approach for commercial synthesis of gefitinib and erlotinib
Chandregowda, Venkateshappa,Rao, Gudapati Venkateswara,Reddy, Goukanapalli Chandrasekara
, p. 813 - 816 (2007)
An efficient, economical and large-scale convergent synthesis of epidermal growth factor receptor- tyrosine kinase inhibitors gefitinib (1, Iressa) and erlotinib (2, Tarceva) approved by U.S. FDA for the treatment of non-small-cell lung cancer is described. The formation of 4-anilinoquinazolines are achieved in a simple one-pot reaction of suitable forniamidine intermediates and substituted anilines involving Dimroth rearrangement, thereby avoiding the need to make quinazolin-4(3H)-one intermediates, which require a large experimental inputs. Using this process, we have produced drug candidates 1 with overall yield of 66% from 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitrobenzonitrile (3) and 2 with 63% from 4-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6) on a multigram scale.
Solubility of two polymorphs of erlotinib hydrochloride in isopropanol and acetone from (273.15 to 303.15) K
Lu, Jie,Zhan, Xiaolan,Chen, Lianwei,Zhang, Lijuan,Mao, Shimin
, p. 2665 - 2669 (2014)
In this work the solubility of two polymorphic forms A and B of erlotinib hydrochloride in isopropanol (IPA) and acetone were determined by means of high-performance liquid chromatography (HPLC) in the temperature range from (273.15 to 303.15) K. The experimental data were correlated with the modified Apelblat equation. In particular, the effect of the surfactant Tween 80 on the solubility of both polymorphs was studied as well. The results show that the solubility of both polymorphs generally increases with the temperature, and polymorph A has a higher solubility than polymorph B which indicates that polymorph A is the metastable form. The modified Apelblat equation shows a good agreement with the experimental data with a percent error less than 3 %. Furthermore, the solubility of both polymorphs increases in a linear fashion with increasing the content of Tween 80 in organic solvents, wherein Tween 80 presents a same solubilization capacity to both polymorphs and a higher solubilization capacity in acetone than in IPA.
Preparation method of erlotinib hydrochloride
-
, (2020/04/01)
The invention relates to a preparation method for erlotinib hydrochloride. The preparation method comprises the following steps: reacting 2-amino-4,5-dimethoxybenzoic acid with formamide to generate acompound 5, carrying out a bromination reaction on the compound 5, and subjecting a bromination product and 3-acetenyl aniline to a reaction and amination to generate a compound 3; and reacting the compound 3 with 48% hydrobromic acid under the action of a catalyst to obtain a compound 2, and reacting the compound 2 with iodoethylmethyl ether under the action of an alkali and the catalyst to generate erlotinib hydrochloride. The method has the advantages of mild conditions, low impurity content, safety, no pollution and environmental protection, and is suitable for industrial production.
Preparation method for high-purity erlotinib hydrochloride
-
Paragraph 0040-0049, (2019/05/16)
The invention belongs to the field of pharmaceutical synthesis, and provides a method for preparing high-purity erlotinib hydrochloride. The method comprises the following steps: 6,7-di(2-methoxyethoxy)quinazoline-4-one is used as a raw material, chlorination is performed to obtain 4-chloro-6,7-di(2-methoxyethoxy)quinazoline (compound I), refining is performed on the compound I, the refined compound I is reacted with 3-aminophenylacetylene, and therefore the high-purity erlotinib hydrochloride is obtained, wherein the purity obtained by HPLC is 99.85% or more, and the content of an impurity 1and an impurity 2 is less than 0.06%. The method provided by the invention is suitable for industrial large-scale production.
