183319-69-9 Usage
Description
Erlotinib hydrochloride, also known as Tarceva, is a quinazoline hydrochloride compound with a (3-ethynylphenyl)amino group at the 4-position and two 2-methoxyethoxy groups at the 6and 7-positions. It is an off-white solid that serves as a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. Erlotinib hydrochloride was developed by Pfizer and OSI, and it is used as an antineoplastic agent, particularly for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) and metastatic pancreatic cancer.
Uses
1. Used in Oncology:
Erlotinib hydrochloride is used as an EGFR inhibitor for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) after the failure of first-line therapy. It is also used as a first-line therapy in combination with gemcitabine for the treatment of metastatic pancreatic cancer and in treating malignant gliomas.
2. Used in Anticancer Applications:
Erlotinib hydrochloride is used as an HER1/EGFR inhibitor with an IC50 of 2 nM, showing more than 1000-fold increased sensitivity for EGFR compared to human c-Src or v-Abl. It is particularly effective against EGFR positive tumors and is beneficial for patients who have never smoked.
3. Used in Drug Development:
Erlotinib hydrochloride is used as a key intermediate in the development of new drugs targeting the epidermal growth factor receptor (EGFR) tyrosine kinase. Its structural similarity to gefitinib allows for improved pharmacokinetic properties, making it a valuable compound in the development of novel anticancer drugs.
4. Used in Pharmaceutical Research:
Erlotinib hydrochloride is used as a research tool for studying the role of EGFR in various cancers and for understanding the mechanisms of action of EGFR inhibitors. It is also used in the development of drug delivery systems to improve the bioavailability and therapeutic outcomes of EGFR-targeted therapies.
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.
Originator
Pfizer (US)
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.
The preparation method of the [...] hydrochloride
-
Paragraph 0023-0036, (2019/06/11)
The invention provides a preparation method for an erlotinib hydrochloride crystal form. The preparation method is as follows: mixing erlotinib free alkaline with an organic solvent, and dropwise adding concentrated hydrochloric acid under a low-temperature condition to obtain high-purity erlotinib hydrochloride crystal form. The preparation method disclosed by the invention has characteristics of being easy in obtaining of materials, controllable in quality (concentrated hydrochloric acid), good in repeatability, simple to operate, high in yield, low in cost, and high in obtained sample purity, is more suitable for industrial production, and has very high economic benefits.