3D Mol Similar

Erlotinib

Iupac Name：N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

CAS No.: 183321-74-6

Molecular Weight：393.443

Modify Date.: 2022-03-20 23:44

Introduction: Erlotinib HCl is an HER1/EGFR inhibitor with IC50 of 2 nM. View more+

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1. Names and Identifiers

1.1 Name: Erlotinib
1.2 Synonyms: 4-[(3-ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline 4-Quinazolinamine, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)- Erlotinib base ERLOTINIB HCL ERLOTINIB HCL SALT Erlotinib Hydrochloirde Erlotinib,OS-774 MFCD07781272 n-(3-ethynylphenyl)[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]amine N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine nchembio866-comp3 OSI 744 Tarceva UNII-J4T82NDH7E

1.3 CAS No.: 183321-74-6

1.4 CID: 176870

1.5 EINECS(EC#): 1312995-182-4

1.6 Molecular Formula: C22H23N3O4 (isomer)

1.7 Inchi: InChI=1S/C22H23N3O4/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)

1.8 InChkey: AAKJLRGGTJKAMG-UHFFFAOYSA-N

1.9 Canonical Smiles: COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC

1.10 Isomers Smiles: COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC

2. Properties

3.1 Density: 1.24

3.1 Melting point: 223 - 228 °C

3.1 Boiling point: 553.6 °C at 760 mmHg

3.1 Refractive index: 1.615

3.1 Flash Point: 288.6 °C

3.1 Precise Quality: 393.16900

3.1 PSA: 74.73000

3.1 logP: 3.47810

3.1 Appearance: white to off-white powder

3.2 Physical: Solid

3.3 pKa: 5.32±0.30(Predicted)

3.4 Water Solubility: very slightly soluble (slightly soluble in methanol, insoluble in acetonitrile, acetone, ethyl acetate, hexane)

3.5 StorageTemp: Keep in dark place,Sealed in dry,Store in freezer, under -20°C

3. Use and Manufacturing

4.1 Definition: ChEBI: A quinazoline compound having a (3-ethynylphenyl)amino group at the 4-position and two 2-methoxyethoxy groups at the 6- and 7-positions.

4.2 GHS Classification: Signal: Danger
GHS Hazard Statements
Aggregated GHS information provided by 7 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (28.57%): Harmful if swallowed [Warning Acute toxicity, oral]
H315 (14.29%): Causes skin irritation [Warning Skin corrosion/irritation]
H319 (14.29%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H335 (14.29%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]
H351 (71.43%): Suspected of causing cancer [Warning Carcinogenicity]
H372 (14.29%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]
H411 (28.57%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]
H413 (71.43%): May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P201, P202, P260, P261, P264, P270, P271, P273, P280, P281, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P314, P321, P330, P332+P313, P337+P313, P362, P391, P403+P233, P405, and P501

4.3 Methods of Manufacturing: Preparation: R.C. Schnur, L.D. Arnold, WO 9630347; eidem, US 5747498 (1996, 1998 both to Pfizer)

4.4 Usage: Erlotinib HCl is an HER1/EGFR inhibitor with IC50 of 2 nM.

4. Safety and Handling

5.1 Safety Statements: 24/25

5.1 Specification: ?Erlotinib , its cas register number 183321-74-6. It also can be called?Tarceva ; UNII-J4T82NDH7E ;?N-(3-Ethynylphenyl)[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]amine ; and 4-[(3-Ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline .?Its classification code are Enzyme Inhibitors and Protein Kinase Inhibitors.

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Carcinogenicity, Category 2

Hazardous to the aquatic environment, long-term (Chronic) - Category Chronic 4

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Warning
Hazard statement(s)	H351 Suspected of causing cancer H413 May cause long lasting harmful effects to aquatic life
Precautionary statement(s)
Prevention	P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P280 Wear protective gloves/protective clothing/eye protection/face protection. P273 Avoid release to the environment.
Response	P308+P313 IF exposed or concerned: Get medical advice/ attention.
Storage	P405 Store locked up.
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

View all

6. NMR Spectrum

13C NMR : Predict

1H NMR : Predict

7. Synthesis Route

183321-74-6Total: 19 Synthesis Route

99-50-3 267 Suppliers

183321-74-6 282 Suppliers

Literatures:
Bulletin of the Korean Chemical Society, , vol. 32, # 3 p. 909 - 914
Yield: null

4101-33-1

183321-74-6 282 Suppliers

Literatures:
WO2011/76813 A1, ;
Yield: null

80407-68-7 13 Suppliers

183321-74-6 282 Suppliers

Literatures:
Bulletin of the Korean Chemical Society, , vol. 32, # 3 p. 909 - 914
Yield: null

View all

8. Precursor and Product

precursor:

183322-18-1

16064-15-6

4296-15-5

4101-33-1

80407-68-7

1312937-40-8

938185-06-9

819813-71-3

179688-29-0

183319-69-9

950596-59-5

99-50-3

236750-65-5

54060-30-9

1312937-41-9

950596-58-4

1011525-96-4

View all

product :

183319-69-9

9. Other Information

9.0 Molecular targeted therapy: The small molecule compound, Erlotinib is a receptor tyrosine kinase inhibitor (EGFR antagonist) and belongs to molecular targeted therapy Drugs. It can inhibit the phosphorylation reaction through competing with adenosine triphosphate to bind to the catalytic region of the receptor tyrosine kinase, thereby blocking the down-proliferation signaling and inhibiting the activity of the tumor cell ligand-dependent HER-1/EGFR, thus achieving the inhibition of the proliferation of tumor cells. Clinically, it is mainly used in the treatment of incurable locally advanced or metastatic non-small cell lung cancer (NSCLC) and being used in combination with gemcitabine for first-line treatment of locally advanced unresectable or metastatic pancreatic cancer.
In November 2004, the product was first approved in the United States for the treatment of local advanced or metastatic non-small cell lung cancer (NSCLC) which has been undergone at least one time of chemotherapy failure.
In 2005, the results of a Phase III trial of the NCI Canadian Clinical Trials Group suggested that gemcitabine, in combination with erlotinib (EGFR blocker) can increase the median survival of patients with advanced pancreatic cancer from 5.9 months to 6.4 months and 1-year survival from 17% to 24%.
In November 2005, Genentech and OSI jointly announced that the US Food and Drug Administration (FDA) had approved the combination of erlotinib (Tarceva) and gemcitabine as first-line treatment for advanced pancreatic cancer.

9.1 Gefitinib: Gefitinib is an aniline quinazoline derivative and is also a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that inhibits the growth, metastasis and angiogenesis of tumors and increases tumor cell apoptosis;
Gefitinib is a kind of highly-specific anti-tumor targeted therapy drugs developed by the United Kingdom AstraZeneca, being the first molecular targeted drug for the treatment of non-small cell lung cancer. It takes effects through selectively inhibiting the signal transduction pathway of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). Epidermal growth factor (EGF) is a polypeptide with a relative molecular mass of 6.45 × 103 that binds to the epidermal growth factor receptor (EGFR) on the target cell membrane to produces biological effects. EGFR is a tyrosine kinase (TK) receptor that, when conjugated to EGF, being capable of promoting the TK activation in the receptor, leading to auto-phosphorylation of the receptor tyrosine residue, providing a continuous signal splitting into the cell, further causing cell proliferation and differentiation. EGFR is abundant in human tissues and highly expressed in malignant tumors. Gefitinib, through interfering with the EGFR signaling transduction pathways on the cell surface, inhibits the tumor growth, metastasis and angiogenesis and induces tumor cell apoptosis.
In August 2002, gefitinib, as a first-line treatment of non-small cell lung cancer drugs, was first listed in Japan under the trade name of Iressa.
In May 2003, the US Food and Drug Administration approved gefitinib as the three-line monotherapy drug for patients with advanced non-small cell lung cancer that can’t be cured by platinum-based anti-cancer drugs and docetaxel chemotherapy. Now, it has been also approved by Australia, Japan, Argentina, Singapore and South Korea and other countries for the treatment of advanced non-small cell lung cancer.
On February 28, 2005, the Chinese Food and Drug Administration approved gefitinib for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) previously subjecting to chemotherapy treatment. It has not yet been approved as a first-line treatment for advanced NSCLC.
On July 1, 2009, the European Union Drug Administration has formally approved gefitinib for the first, second and third line treatment of adult EGFR mutations locally advanced or metastatic non-small cell lung cancer.

9.2 Dosage and Usage: Non-small cell lung cancer: 150mg/d; administrate at least1h before meals or 2h after meal; continue taking the drug until the disease get progression or the emergence of intolerable toxicity response when the patients should withdraw the drug.
Pancreatic cancer: combine with gemcitabine for 100mg /d at least 1h before meals or 2h after meals; continue taking the drug until the disease get progression or the emergence of intolerable toxicity response when the patients should withdraw the drug.
Upon severe liver insufficiency, the drug dosage should be reduced or temporarily discontinued, elderly patients do not have to adjust the dose.

9.3 Clinical evaluation: Erlotinib is another tyrosine kinase inhibitor for the treatment of NSCLC after imatinib. The phase I clinical trial results have shown that its main toxicity and side effects are dose-dependent rash and diarrhea. Other rare side effects also include headache, nausea and vomiting.
Phase II trial takes erlotinib as a second line antineoplastic drugs with the efficacy being comparable as the second-line chemotherapy drug docetaxel. The Phase III randomized controlled trial (BR21) was performed in patients with NSCLC who had failed in the primary or secondary chemotherapy (locally advanced and distant metastases). Study group applied erlotinib in a dosage of 150mg daily for treatment of a total of 488 cases. A total of 243 cases were treated with placebo in the control group. The result: the median overall survival rate was 6.7 months in the treatment group and 4.7 months in the control group (P <0.001, HR = 0.73). The 1-year survival rate was 31.2% in the treatment group and 21.5% in the control group; the time of progression was 9.9 weeks in treatment group and 7.9 weeks in control group while the improvement of symptoms in patients with erlotinib was more obvious.
Based on the results of BR21 research, a number of phase Ⅲ clinical studies have been carried out successively. TRIBUTE clinical trial combined the Erlotinib with chemotherapy in an attempt to compare whether the efficacy of its combination with chemotherapy is better than chemotherapy alone. For the treatment group, chemotherapy (carboplatin plus paclitaxel) + erlotinib were combined; for the control group, the same chemotherapy was used alone. A total of 1059 patients with advanced NSCLC were included in the study. The efficacy in the research result: 21.5% for research group; 19.3% for the control group. The median survival time was 10.8 months in the study group and 10.6 months in the control group. The time to tumor progression (TTP) was 5.1 months in the study group and 5.0 months in the control group. Another TALENT study also focused on whether the combination of erlotinib and chemotherapy (gemcitabine + cisplatin) can improve the efficacy of chemotherapy and have included a total of 1172 cases of NSCLC patients. The results also did not show that erlotinib can significantly improve the efficacy of chemotherapy.

9.4 Adverse reactions and precautions: Common adverse reactions include rash, fever, anorexia, indigestion, nausea, vomiting, diarrhea, constipation and abdominal pain, fatigue, weight loss and edema, bone pain and muscle pain, dyspnea, elevated transaminases. In rare cases, it was observed of bone marrow suppression. Oral administration of warfarin may lead to unexpectedly increased international standardization ratio. There are occasionally chills, cough, stomatitis, keratoconjunctivitis, anxiety and neurological diseases, elevated bilirubin. In rare cases, there are microangiopathies hemolytic anemia and thrombocytopenia. Cough and fever may be associated with interstitial lung disease, if it occurs, the drugs should be discontinued. Cytochrome P450 enzymes affect the metabolism of the product. Its inhibitor ketoconazole or agonist rifampicin can change the plasma concentration of this product, resulting in increased toxicity or reduced toxicity. Patients of co-administration of warfarin should subject to closely monitoring of the international normalized ratio.

9.5 Clinical evaluation: Erlotinib is another tyrosine kinase inhibitor for the treatment of NSCLC after imatinib. The phase I clinical trial results have shown that its main toxicity and side effects are dose-dependent rash and diarrhea. Other rare side effects also include headache, nausea and vomiting.
Phase II trial takes erlotinib as a second line antineoplastic drugs with the efficacy being comparable as the second-line chemotherapy drug docetaxel. The Phase III randomized controlled trial (BR21) was performed in patients with NSCLC who had failed in the primary or secondary chemotherapy (locally advanced and distant metastases). Study group applied erlotinib in a dosage of 150mg daily for treatment of a total of 488 cases. A total of 243 cases were treated with placebo in the control group. The result: the median overall survival rate was 6.7 months in the treatment group and 4.7 months in the control group (P <0.001, HR = 0.73). The 1-year survival rate was 31.2% in the treatment group and 21.5% in the control group; the time of progression was 9.9 weeks in treatment group and 7.9 weeks in control group while the improvement of symptoms in patients with erlotinib was more obvious.
Based on the results of BR21 research, a number of phase Ⅲ clinical studies have been carried out successively. TRIBUTE clinical trial combined the Erlotinib with chemotherapy in an attempt to compare whether the efficacy of its combination with chemotherapy is better than chemotherapy alone. For the treatment group, chemotherapy (carboplatin plus paclitaxel) + erlotinib were combined; for the control group, the same chemotherapy was used alone. A total of 1059 patients with advanced NSCLC were included in the study. The efficacy in the research result: 21.5% for research group; 19.3% for the control group. The median survival time was 10.8 months in the study group and 10.6 months in the control group. The time to tumor progression (TTP) was 5.1 months in the study group and 5.0 months in the control group. Another TALENT study also focused on whether the combination of erlotinib and chemotherapy (gemcitabine + cisplatin) can improve the efficacy of chemotherapy and have included a total of 1172 cases of NSCLC patients. The results also did not show that erlotinib can significantly improve the efficacy of chemotherapy.

9.6 Description: Erlotinib is a tyrosine kinase inhibitor which acts on the epidermal growth factor receptor (EGFR), inhibiting EGFR-associated kinase activity (IC₅₀ = 2.5 μM). This inhibits tumor growth in human head and neck carcinoma HN5 tumor xenografts in mice with an ED₅₀ value of 9 mg/kg. Erlotinib also suppresses cyclin-dependent kinase 2 (Cdk2) activity in breast cancer cells (IC₅₀ = 4.6 μM) and JAK2 mutant JAK2^V617F positive hematopoietic progenitor cells (IC₅₀ = 5 μM), which is associated with polycythemia vera, idiopathic myelofibrosis, and essential thrombocythemia. Formulations containing erlotinib have been used to treat certain forms of cancer, including non-small cell lung cancer.

9.7 What is molecular targeted therapy?: Molecular targeted therapy is no longer a new term. Scientists are constantly exploring the pathogenesis of cancer molecular biology, realizing that if specific changes in cancer can be given by a powerful blow, it will greatly improve the treatment effect, triggering changes in anti-cancer treatment concept. In recent years, new molecular targeted drugs in clinical practice have achieved remarkable results. The practice has shown that the correctness and feasibility of the molecular targeted therapy theory, putting the cancer treatment to an unprecedented new stage.
Depending on the target and nature of the drug, the drugs of the major target molecule therapy can be divided into the following categories:
(1) Small molecule tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR): such as gefitinib (Iressa), Erlotinib (Tarceva);
(2) anti-EGFR monoclonal antibody: such as cetuximab (Erbitux);
(3) Anti-HER-2 monoclonal antibody: such as Herceptin (Trastuzumab);
(4) Bcr-Abl tyrosine kinase inhibitors: such as imatinib;
(5) Vascular endothelial growth factor receptor inhibitors: such as Bevacizumab (Avastin);
(6) anti-CD20 monoclonal antibody: such as rituximab (Rituximab);
(7) IGFR-1 kinase inhibitors such as NVP-AEW541;
(8) mTOR kinase inhibitors: such as CCI-779;
(9) Ubiquitin-proteasome inhibitors: such as Bortezomib;
(10) Other: such as Aurora kinase inhibitors, histone deacetylase (HDACs) inhibitors.

9.8 Uses: Erlotinib HCl is an HER1/EGFR inhibitor with IC50 of 2 nM.

9.9 Uses: antineoplastic;tyrosine kinase inhibitor

9.10 Uses: A tyrosine kinase inhibitor

9.11 Definition: ChEBI: A quinazoline compound having a (3-ethynylphenyl)amino group at the 4-position and two 2-methoxyethoxy groups at the 6- and 7-positions.

9.12 Brand name: Tarceva (OSI).

10. Computational chemical data

Molecular Weight: 393.443g/mol
Molecular Formula: C₂₂H₂₃N₃O₄
Compound Is Canonicalized: True
XLogP3-AA: 3.3
Exact Mass: 393.16885622
Monoisotopic Mass: 393.16885622
Complexity: 525
Rotatable Bond Count: 11
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 7
Topological Polar Surface Area: 74.7
Heavy Atom Count: 29
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADceB7OAAAAAAAAAAAAAAAAAAAAAAAAAA8YIAAAAAAAACx9AAAHgAQAAAADAyhngY39vbIFADgGyZjZAiCiCkxIqAJ2CA+7JiNLuLE+duGPCru0BvK6Cew0BMOIEABQgACQABAgAKEAASAAAAAAAAAAA==

12. Realated Product Infomation

938185-06-9 Erlotinib

183320-72-1 Erlotinib

183322-38-5 Erlotinib

1384975-87-4 Erlotinib

1027829-73-7 erlotinib

183319-69-9 Erlotinib hydrochloride

183321-85-9 Erlotinib impurity A

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