184475-35-2 Usage
Uses
Used in Oncology:
Gefitinib is used as an antineoplastic agent for the treatment of inoperable or recurrent non-small cell lung cancers (NSCLC). It has been shown to induce a response rate approaching 20% in patients receiving the agent as a second-line therapy and approximately 10% in those pretreated with more lines of chemotherapy.
Used in Endometrial Cancer Therapy Research:
Gefitinib has been used to study its effective use in endometrial cancer therapy through cell proliferation, cell cycle, and apoptosis assays, as well as cell viability assay and colony formation assay.
Used in the Treatment of Squamous Cell Cancers:
Gefitinib is available as 250-mg tablets for oral administration in the treatment of NSCLC for patients who have failed to respond to platinum-based therapies and docetaxel. It has also been used against squamous cell cancers of the head and neck.
Chemical Properties:
Gefitinib is a light-yellow crystalline powder.
Brand Name:
Iressa (AstraZeneca).
Indications and Uses
Gefitinib is an antineoplastic target therapy drug with relatively high specificity that was developed by the British pharmaceutical company AstraZeneca; it is the first molecular targeted drug to be used in non-small cell lung cancer treatment. Epidermal growth factors (EGF) are a kind of polypeptide with a relative molecular mass of 6.45x103, and they can bind with epidermal growth factor receptors (EGFR) on target cell membrane surfaces to trigger biological effects. EGFR is a type of tyrosine kinase (TK) type receptor, so when bound with EGF, it will promote TK activation in the receptor. This will cause tyrosine residue in the receptor to autophosphorylate and send continuous dividing signals into the cell, causing cell proliferation and differentiation. EGFR is abundant in human tissue, and it is highly expressed in malign tumors. Gefitinib blocks the signal transduction pathway of cell surface EGFR to prevent tumor growth, metastasis, and growth in blood vessels, and it can induce tumor cell apoptosis. Gefitinib is mainly used to treat non-stem cell lung cancer.
Pharmacokinetics
It is orally effective, with relatively slow absorption and metabolism following intake. The bioavailability of a single oral 250mg dose is nearly 60%, and its area under curve (AUC) is dependent on dosage. With single daily dosages, blood concentration is steady after 7-10 days, with blood concentration peaking 3-7 hours after medication and then gradually following biphasic reduction (its half-life is 12-58 hours, at an average of 28 hours). It is observed as dose-dependent pharmacokinetics, and following multiple dosages, AUC and Cmax increased proportionally. When taken with food, its Cmax and AUC did not decrease significantly. Its plasma protein binding rate is nearly 90%. Gefitinib is metabolized through many different pathways in the livers in a relatively complicated process; the main component of its oxidative metabolism is the cytochrome P450 enzyme CYP3A4, which mainly metabolizes O-Desmethyl metabolites. Metabolites are unrelated to the pharmacological effects of the original drug. The original drug and many metabolites are mostly passed through the biliary tract and excreted through feces, while the amount of drug excreted through urine is less than 4% the original dosage amount.
Adverse Reactions
Gefitinib is relatively well-tolerated, and most negative reactions are mild and reversible, characteristics that are vastly different from those of standard negative reactions to cytotoxic drugs. Common negative reactions include diarrhea, nausea, rashes, acne, vomiting, and feebleness. Only 1% of patients have had to cease treatment due to negative reactions with an occurrence rate over 20%. There have also been rare cases of acute interstitial pneumonia.
Warnings and precautions
Gefitinib is not suitable for pregnant women, and breastfeeding women should cease breastfeeding throughout their treatment period.
Originator
Astra Zeneca (UK)
Indications
Iressa (ZD1839) is an orally active tyrosine kinase inhibitor
selective for the epidermal growth factor (EGF)
receptor tyrosine kinase. Iressa is undergoing clinical
trials in the treatment of various solid tumors, including
head and neck cancer, breast cancer and non-small cell
lung cancer. Its antitumor activity is derived from the
fact that the EGF receptor and EGF signaling are
frequently overactivated in sensitive tumors. The major
side effects include diarrhea and skin rash. Bone marrow
toxicity has not been a dose-limiting problem.
Indications
The EGFR or ErbB1 inhibitor gefitinib (Iressa(R), AstraZeneca) was originally approved by the US FDA in 2003 under accelerated regulations for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after progression on docetaxel- and platinum-based chemotherapy. AstraZeneca voluntarily withdrew gefitinib from the market in 2005, owing to failed verification of clinical benefit during post-approval studies. In July 2015, FDA reinstated the approval of gefitinib for a different group of patients (i.e., NSCLC patients with EGFR mutations).
Other approved kinase inhibitors targeting the ErbB family, which includes ErbB1/EGFR, ErbB2/human epidermal growth factor receptor 2 (Her2), ErbB3/ Her3, and ErbB4/Her4, are erlotinib (Tarceva(R), OSI Pharm.), lapatinib (Tykerb(R), GlaxoSmithKline), vandetanib (Caprelsa(R), AstraZeneca), afatinib (Gilotrif(R), Boehringer Ingelheim) , and osimertinib (Tagrisso(R), AstraZeneca). All approved EGFR family inhibitors share a common quinazoline scaffold with the exception of osimertinib, which has a pyrimidinylphenylamine scaffold that resembles that of imatinib and nilotinib. Gefitinib and vandetanib adopt the type I binding mode with “DFG-in” and αC-helix “in” conformation, while erlotinib and lapatinib bind to“DFG-in”with the αC-helix adopting an “out” conformation. Afatinib and osimertinib are covalent inhibitors with an electrophilic enone moiety.
Biological Activity
Orally active, selective inhibitor of EGFR tyrosine kinase (IC 50 = 23-79 nM). Shows minimal activity against ErbB2, KDR, c-flt, PKC, MEK and ERK-2. Blocks EGFR autophosphorylation and inhibits tumor growth in mice bearing a range of human xenografts.
Biochem/physiol Actions
Gefitinib is a selective epidermal growth factor receptor tyrosine kinase (EGFR TK) inhibitor. Gefitinib has antineoplastic activity, and has been approved for the treatment on non-small cell lung cancer (NSCLC).Gefitinib has a higher affinity for ATP (adenosine triphosphate) binding site in the EGFR tyrosine kinase domain than ATP. Hence, gefitinib is known to inhibit the progression of endometrial cancer.
Clinical Use
Tyrosine kinase inhibitors:
Treatment of non-small cell lung cancer
Synthesis
A mixture of 4,5-dimethoxyanthranilic acid
(133) and formamide was heated to generate the cyclized
quinazoline 134. The quinazoline was selectively monodemethylated with methionine in refluxing methanesulfonic
acid to afford 135 in 47% yield. Compound 135 was
acylated to give acetate 136, which was treated with
refluxing thionyl chloride to yield chloropyrimidine 137.
Chloride 137 was condensed with 3-chloro-4-fluoroaniline
(138) in refluxing IPA to yield anilinoquinazoline 139 in
56% yield from 136. The acetate protecting group in
compound 139 was hydrolyzed with ammonium hydroxide
in methanol, and the free phenol was alkylated with 3-(4-
morpholinyl)propyl chloride (140) to give gefitinib (13) in
55% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: Avoid with rifampicin (reduced
gefitinib concentration).
Anticoagulants: possibly enhanced anticoagulant
effect with warfarin
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis).
Antivirals: avoid with boceprevir.
Ulcer-healing drugs: concentration reduced by
ranitidine.
Avoid concomitant use with other inhibitors or
inducers of CYP3A4. Dose alterations may be
required.
Metabolism
Extensively metabolised in the liver, mainly by the
cytochrome P450 isoenzymes CYP3A4 and CYP2D6;
the major metabolite is O-desmethylgefitinib, which is
much less potent than gefitinib, and unlikely to contribute
to its clinical activity.
Gefitinib is excreted mainly as metabolites via the faeces
(86%); renal elimination of gefitinib and its metabolites
accounts for <4% of the dose.
References
1) Baselga et al. (2000), ZD1839 (‘Iressa’) as an anticancer agent; Drugs, 60 33
2) McKillop et al. (2005), Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; Mol. Cancer Ther., 4 641
3) Sirotnak et al. (2000), Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase; Clin. Cancer Res., 6 4885
4) Ciaradiello et al. (2001), Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor; Clin. Cancer Res., 7 1459
Check Digit Verification of cas no
The CAS Registry Mumber 184475-35-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,8,4,4,7 and 5 respectively; the second part has 2 digits, 3 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 184475-35:
(8*1)+(7*8)+(6*4)+(5*4)+(4*7)+(3*5)+(2*3)+(1*5)=162
162 % 10 = 2
So 184475-35-2 is a valid CAS Registry Number.
InChI:InChI=1/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
184475-35-2Relevant articles and documents
Novel preparation of gefitinib
Zheng, Youguang,Li, Mingdong,Zhang, Shaoning,Ji, Min
, p. 388 - 390 (2009)
A new synthesis of the anticancer drug gefitinib is described starting from methyl 3-hydroxy-4-methoxybenzoate.The sequence involves alkylation of the starting material, followed by nitration, reduction, cyclisation, chlorination and amination reactions.
Synthesis of gefitinib from methyl 3-hydroxy-4-methoxy-benzoate
Ming, Dong Li,You, Guang Zheng,Ji, Min
, p. 673 - 678 (2007)
This paper reports a novel synthesis of gefitinib starting from methyl 3-hydroxy-4-methoxybenzoate. The process starts with alkylation of the starting material, followed by nitration, reduction, cyclization, chlorination and two successive amination reactions. The intermediates and target molecule were characterized by 1H-NMR, 13C-NMR, MS and the purities of all these compounds were determined by HPLC. This novel synthetic route produced overall yields as high as 37.4%.
Improved protocol for synthesis of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy) quinazolin-4-amine (gefitinib)
Kumar, Pawan,Mazlee, Muhammad Taufiq F.,Abdul Wahab, Muhammad K.,Belwal, Chandra Kant,Kumar, Ramesh,Sajid, Shahnawaz
, p. 39 - 46 (2019)
An improved three-step process for the synthesis of gefitinib from readily available starting material is discussed in this protocol. The protocol is based on the synthesis, isolation, characterization of novel intermediates and their application in the alkylation step for the synthesis of gefitinib. Excellent results were achieved over the conventional synthetic methodologies. Isolation of these intermediates were effective in replacing high boiling solvent with low boiling solvent(s) but also in eliminating base from the reaction. These conditions led to effective elimination of all the prior art reported impurities. This high-yielding process is cost-effective with isolable and stable intermediates. These intermediates were characterized using NMR, mass spectroscopy, DSC and XRPD analyses.
Synthesis of [11C]Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase
Wang, Ji-Quan,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
, p. 4102 - 4106 (2006)
Iressa (Gefitinib) is an orally active inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) involved in cell signal transduction processes critical to proliferation, apoptosis, repair, and angiogenesis of cancer cells. [11C]Iressa was first designed and synthesized as a new potential positron emission tomography (PET) cancer imaging agent for EGFR-TK in 30-40% radiochemical yield with 4.0-6.0 Ci/μmol specific activity at end of bombardment (EOB).
A new synthesis of gefitinib
Maskrey, Taber S.,Kristufek, Tyler,Laporte, Matthew G.,Nyalapatla, Prasanth R.,Wipf, Peter
, p. 471 - 476 (2019)
A four-step synthesis of the FDA-approved anticancer agent gefitinib was developed starting from 2,4-dichloro-6,7-dimethoxyquinazoline. Reaction temperatures were highly practical (0-55 °C), and chromatographic purifications were avoided. The ionic liquid trimethylammonium heptachlorodialuminate was used to monodemethylate the dimethoxyquinazoline core. In the final step, a selective dehalogenation was employed to provide gefitinib in 14% overall yield on a gram scale.
A Different Approach to the EGFR Inhibitor Gefitinib Involving Solid-Phase Synthesis
Sequeira, André,Louren?o, Ana,Ferreira, Luísa Maria,Branco, Paula Sério,Mendes, Zita,Louren?o, Nuno M. T.,Figueiredo, Margarida,Carvalho, Luísa C. R.
, p. 1346 - 1350 (2018)
An efficient solid-phase synthesis approach is here reported for the first time to prepare the EGFR inhibitor Gefitinib. The five-step synthetic strategy used FMP resin as the solid support, and FTIR and colorimetric assays were used to track the reaction's progress. Gefitinib was obtained with an overall yield of 40%.
Method suitable for industrial production and preparation of gefitinib
-
Paragraph 0022; 0032, (2021/08/19)
The invention discloses a method suitable for industrial production and preparation of gefitinib, which takes 6, 7-dimethoxy-3H-quinazoline-4-one as a raw material, and gefitinib is obtained through four steps of chlorination, amination, demethylation and reaction with N-(3-chloropropyl) morpholine, so as to solve the problems that the existing synthetic route is complex and long, the total yield is low, a large number of environment-unfriendly reagents are used, and the technology cannot be amplified. According to the method, pyridine hydrochloride/DMSO is utilized to remove 6-position methyl in a high-selectivity manner, a key intermediate N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazoline-4-amine is obtained in a high yield manner, and convenient synthesis of the intermediate is realized. The synthesis method has the advantages of cheap and easily available raw materials and short route, and gefitinib and derivatives modified by different 6-site groups can be rapidly obtained. The preparation method solves the bottleneck problem of large-scale production of the active pharmaceutical ingredient gefitinib.
Synthesis of gefitinib
-
Paragraph 0021-0026, (2021/09/29)
The invention relates to preparation of gefitinib. Specifically, 3-morpholine propane-1-ol (formula I) reacts with 6-halogenated-N-(4-chloro-2-fluorophenyl)-7-methoxyquinazoline-4-amine (formula II) in the presence of a copper reagent, an alkali, an additive and a solvent, so the preparation of the gefitinib is realized.
Purification process of gefitinib
-
Paragraph 0038; 0045-0085, (2020/08/25)
The invention provides a purification process of gefitinib. The purification process comprises the following steps: adding potassium carbonate, potassium iodide and a gefitinib intermediate 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-ol into N, N-dimethylformamide, stirring, heating to 70 DEG C, adding N-(3-chloropropyl)morpholine, reacting to obtain a gefitinib reaction solution, adding diluted hydrochloric acid into the gefitinib reaction solution, cooling to room temperature, adding sodium chloride, stirring for crystallization, filtering to obtain filter cake, adding the filter cakeinto a sodium bicarbonate solution, carrying out alkali washing, and recrystallizing the obtained product in ethanol to obtain high-purity gefitinib. The purification process is simple in process, and the obtained gefitinib product is high in purity.
Synthesis method of tumor cell inhibition drug
-
Paragraph 0042; 0052-0053; 0054; 0064-0065, (2020/02/29)
The invention relates to the technical field of organic synthesis and drugs, and discloses a synthesis method of a tumor cell inhibition drug. 3-hydroxy-4-methoxybenzaldehyde is taken as a starting raw material, aldehyde ortho-hydrogen is activated through a temporary guide group to facilitate amino substitution, [4 + 2] cyclization addition reaction is combined for cyclization, and introduction of a propyl morpholine side chain to a hydroxyl group, chlorination and introduction of a fluorochloroaniline side chain are sequentially carried out to finally prepare gefitinib. The synthesis path ofthe tumor cell inhibition drug gefitinib reduces reaction steps, shortens the reaction time, reduces the production cost, reduces the generation of impurities in the system, and reduces the emissionof three wastes.
