Regorafenib

Iupac Name：4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide

Molecular Weight：482.82

Modify Date.: 2022-11-25 01:18

Introduction: It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent. View more+

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1. Names and Identifiers

1.1 Name: Regorafenib
1.2 Synonyms: 2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino] carbonyl]amino]-3-fluorophenoxy]-N-methyl- 2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-N-methyl- 4-(4-(3-(4-chloro-3-(trifluoroMethyl)phenyl)ureido)-3-fluorophenoxy)-N-MethylpicolinaMide 4-[4-({[4-chioro-3-(trifluoroMethyl)phenyl]carbaMoyl}aMino)-3-fluorophenoxy]-pyridine-2-carboxylic acid MethylaMide 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl-2-pyridinecarboxamide 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide BAY 73-4506 BAY 73-4506(Regorafenib) BAY734506 BAY73-4506 Regorafenib (BAY 73-4506) REGORAFENIB BAY 73-4506 BAYER HEALTHCARE (SEE ALSO COLORECTAL, LUNG, STOMACH) PHASE II(REGORAFENIB) PHARMACEUTICALS (888) 842-2937WAYNE, NJ Stivarga

1.3 CAS No.: 755037-03-7

1.4 CID: 11167602

1.5 EINECS(EC#): 815-051-1

1.6 Molecular Formula: C21H15ClF4N4O3 (isomer)

1.7 Inchi: InChI=1S/C21H15ClF4N4O3/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26/h2-10H,1H3,(H,27,31)(H2,29,30,32)

1.8 InChkey: FNHKPVJBJVTLMP-UHFFFAOYSA-N

1.9 Canonical Smiles: CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F

1.10 Isomers Smiles: CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F

2. Properties

2.1 Density: 1.491

2.1 Melting point: 206.0 to 210.0 °C

2.1 Boiling point: 513.4 °C at 760 mmHg

2.1 Refractive index: 1.616

2.1 Flash Point: 264.3 °C

2.1 Precise Quality: 482.07700

2.1 PSA: 92.35000

2.1 logP: 6.22570

2.1 Appearance: White to Light yellow to Light orange powder to crystal

2.2 pKa: 12.04±0.70(Predicted)

2.3 Water Solubility: Insoluble

2.4 StorageTemp: <0°C

3. Use and Manufacturing

3.1 Definition: ChEBI: A pyridinecarboxamide obtained by condensation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxylic acid with methylamine. Used for for the treatment of metastatic colorectal cancer in patients who have previusly received chemotherapy, anti-EGFR or anti-VEGF therapy.

3.2 Usage: It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent.

4. Safety and Handling

4.1 Hazard Declaration: H360

4.1 Caution Statement: P201, P202, P260, P263, P264, P270, P273, P281, P308+P313, P314, P391, P405, P501

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

no data available

2.2 GHS label elements, including precautionary statements

Pictogram(s)	no data available
Signal word	no data available
Hazard statement(s)	no data available
Precautionary statement(s)
Prevention	no data available
Response	no data available
Storage	no data available
Disposal	no data available

2.3 Other hazards which do not result in classification

no data available

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6. Synthesis Route

755037-03-7Total: 5 Synthesis Route

399-95-1 180 Suppliers

755037-03-7 203 Suppliers

Literatures:
WO2011/128261 A1, ;
Yield: null

394-41-2 143 Suppliers

755037-03-7 203 Suppliers

Literatures:
WO2011/130728 A1, ; WO 2011/130728 A1
Yield: null

1338722-53-4 1 Suppliers

755037-03-7 203 Suppliers

Literatures:
WO2011/128261 A1, ;
Yield: null

View all

7. Precursor and Product

precursor:

399-95-1

1338722-53-4

1338722-52-3

394-41-2

757251-39-1

327-78-6

product :

835621-07-3

8. Other Information

8.0 Livertox Summary: Regorafenib is an oral multi-kinase inhibitor that is used in the therapy of refractory metastatic colorectal cancer, hepatocellular carcinoma and gastrointestinal stromal tumor. Regorafenib has been associated with frequent serum aminotransferase elevations during therapy and with rare, but sometimes severe and even fatal instances of clinically apparent liver injury.

8.1 Drug Classes: Antineoplastic Agents

8.2 Absorption: Cmax = 2.5 μg/mL; Tmax = 4 hours; AUC = 70.4 μg*h/mL; Cmax, steady-state = 3.9 μg/mL; AUC, steady-state = 58.3 μg*h/mL; The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.|Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.|Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval.

8.3 Metabolism: Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively). Regorafenib is an inhibitor of P-glycoprotein, while its active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) are substrates of P-glycoprotein.

8.4 Biological Half Life: Regorafenib, 160 mg oral dose = 28 hours (14 - 58 hours); M2 metabolite, 160 mg oral dose = 25 hours (14-32 hours); M5 metabolite, 160 mg oral dose = 51 hours (32-72 hours);

8.5 Mesh Entry Terms: 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)-3-fluorophenoxy)-n-methylpyridine-2-carboxamide

8.6 Use Classification: Human drugs -> Stivarga -> EMA Drug Category|Antineoplastic agents, Protein kinase inhibitors -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

8.7 Side effects: Regorafenib is being approved with a Boxed Warning alerting patients and health care professionals that severe and fatal liver toxicity occurred in patients treated with regorafenib during clinical studies. Serious side effects, which occurred in less than one percent of patients, were liver damage, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks and perforations (holes) in the intestines. The most common side effects reported in patients treated with regorafenib include weakness or fatigue, loss of appetite, hand-foot syndrome (also called palmar-plantar erythrodysesthesia), diarrhoea, mouth sores (mucositis), weight loss, infection, high blood pressure, and changes in voice volume or quality (dysphonia).

8.8 Small Molecule Inhibitor: Regorafenib (BAY 73-4506, Stivarga ) is a new oral small molecule multi-kinases inhibitor. It can inhibit the target kinases associated with angiogenesis and tumorigenesis. The pathway influenced by regorafenib and the biomarkers for monitoring the efficacy of regorafenib become hot spots. Because of its wide spectrum kinase inhibitory activity, the utilization of regorafenib in many clinical indications are also carried out extensively. Since regorafenib is approved with the box warning, its side effects can not be ignored.

8.9 FDA Approve: Regorafenib (BAY73-4506) is a new type of multikinase inhibitor developed by Bayer, and is the first small molecule kinase inhibitor approved by the U.S. FDA on September 27, 2012 used for fast track colorectal cancer that develops and metastases after conventional treatment.
Regorafenib achieves good results in some patients with rectal cancer that are resistant to traditional chemotherapy, but not all rectal cancers are sensitive to it. Therefore, the pathway influenced by regorafenib and the biomarkers for monitoring the efficacy of regorafenib become hot spots.

8.10 Description: In September 2012, theUSFDAapproved regorafenib for the treatment of patients with metastatic colorectal cancer (CRC), especially those for whom standard therapies have failed, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, ananti-EGFRtherapy. Regorafenib is a multikinase inhibitor with potent inhibitory activity versus VEGFRs and PDFRs. Both of these classes of receptors are expressed on tumor cells and affect proliferation and angiogenesis. Regorafenib inhibited growth in murine xenograft models for colon, breast, renal, lung, melanoma, pancreatic, and ovarian tumors when dosed at 10–30 mg/kg. Regorafenib is a fluorinated analog of sorafenib, a multikinase inhibitor co-marketed by Bayer and Onyx for the treatment of kidney and liver cancer. The synthesis of regorafenib is accomplished in two steps from commercially available starting materials. 4-Aminophenol is coupled to 4-chloro-N-methyl- 2-pyridinecarboxamide to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. Subsequent treatment with 4-chloro-3-(trifluoromethyl)phenyl isocycanate affords the urea, regorafenib.

8.11 Description: Regorafenib is an orally bioavailable multi-kinase inhibitor with anticancer activity. It inhibits RET, C-RAF, VEGFR2, c-Kit, VEGFR1, and PDGFRβ with IC₅₀ values of 1.5, 2.5, 4.2, 7, 13, and 22 nM, respectively. Regorafenib also inhibits B-RAF, VEGFR3, FGFR, and Tie2 (IC₅₀s = 28, 46, 202, and 311 nM, respectivey) as well as other kinases. In vivo, regorafenib (10 mg/kg) reduces tumor size in the MDA-MB-231 breast and 786-O renal cancer mouse xenograft models. It also reduces tumor microvessel area and inhibits tumor growth in a panel of mouse xenograft models. Formulations containing regorafenib have been used in the treatment of advanced gastrointestinal stromal tumors and metastatic colorectal cancer.

8.12 Originator: Bayer (Germany)

8.13 Uses: It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent.

8.14 Uses: BAY 73-4506 (Regorafenib) is a multikinase inhibitor with IC50 of 17, 40 and 69 nM c-KIT, VEGFR2, B-Raf.

8.15 Uses: Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively

8.16 Definition: ChEBI: A pyridinecarboxamide obtained by condensation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxylic acid with methylamine. Used for for the treatment of metastatic colorectal cancer in patients who have previ usly received chemotherapy, anti-EGFR or anti-VEGF therapy.

8.17 Brand name: Stivarga

9. Computational chemical data

Molecular Weight: 482.82g/mol
Molecular Formula: C₂₁H₁₅ClF₄N₄O₃
Compound Is Canonicalized: True
XLogP3-AA: 4.2
Exact Mass: 482.0768807
Monoisotopic Mass: 482.0768807
Complexity: 686
Rotatable Bond Count: 5
Hydrogen Bond Donor Count: 3
Hydrogen Bond Acceptor Count: 8
Topological Polar Surface Area: 92.4
Heavy Atom Count: 33
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: AAADccB7scAEAAAAAAAAAAAAAAAAAAAAAAA8YIAAAAAAAAAB0AAAHwIQAAAADA7Bnjw/xpLIFACoAzV3VACCiCA3JyAI2KG+btiMZnLFt7uWOSju1hvI6ae6yAAOAEBAQAABAAAAgICAAAIAAAAAAAAAAA==

10. Question & Answer

What is Regorafenib? Sep 14 2020
Figure 1. Chemical formula of regorafenib Regorafenib—a small molecule tyrosine kinase inhibitor, which molecular formula is C21H15ClF4N4O3•H2O, and the molecular weight is 500.83. The chemical structural formula of reforafenib is shown in Figure 1. It is almost insoluble in water, sligh...

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