Foretinib

Foretinib is a multi-target tyrosine kinase inhibitor with IC50s of 0.4 nM and 0.9 nM for Met and KDR.

N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is an aromatic ether.|Foretinib has been used in trials studying the treatment of Cancer, Breast Cancer, Carcinoma, Renal Cell, Recurrent Breast Cancer, and Neoplasms, Head and Neck, among others. Foretinib is an orally available small molecule compound designed to target multiple RTKs implicated in the development, progression and spread of cancer. It inhibits the activation of MET, RON, ERK and AKT, decreased proliferation and increased apoptosis.|Foretinib is an orally bioavailable small molecule with potential antineoplastic activity. Foretinib binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. The proto-oncogene c-MET has been found to be over-expressed in a variety of cancers. VEGFR2 is found on endothelial and hematopoietic cells and mediates the development of the vasculature and hematopoietic cells through VEGF signaling.

Further Preparation and Characterization of Crystalline N-[3- fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'- ( 4-fIuorophenyl Cyclopropane- 1, 1 -dicarboxamide. Compound (I), Form B.[0078] 3.1: Preparation of Compound (I), Crystalline Form B. [0079] To a dried reactor (reactor 1 ) was added 1 -(4-fluorophenyl carbamoyl)cyclopropane carboxylic acid (21.5 kg), THF (76 kg), and N, N- dimethylformamide (DMF, 0.09 kg) which was agitated at 20 To a mechanically stirred slurry of cyclopropane-l, 1-dicarboxylic acid [3-FLUORO-4- (7-HYDROXY-6-METHOXY- quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl) -amide (16.6 g, 32. 8 mmol) and potassium carbonate (13.6 g, 98.6 mmol) in DMF (250 mL) was added 4- (3- chloropropyl) -morpholine hydrochloride (13, 7. 92 g, 39.6 mmol). The resulting mixture was heated at 90°C for 5 hours (until phenol completely consumed). The reaction mixture was allowed to cool to room temperature, then dumped into water (900 mL), followed by extraction with EtOAc (3X). The combined extracts were washed with 5percent LiCl (aq. ) (3X) and brine (1X) followed by drying over MGS04 and concentration in vacuo. The crude (18.8g) obtained as brown solid was further purified by flash chromatography [silica gel, 4-stage gradient system: 1) EtOAc; 2) EtOAc: MeOH: 7N NH3/MEOH (95: 5: 0.5) ; 3) DCM: MeOH: 7N NH3/MeOH (95: 5: 0.5) ; 4) DCM: MeOH : 7N NH3/MeOH (93: 8 : 1)], affording N- [3-FLUORO-4- ( {6- (METHYLOXY)-7- [ (3-MORPHOLIN-4-YLPROPYL) OXY] QUINOLIN-4- YL} OXY) PHENYL]-N-(4-FLUOROPHENYL) CYCLOPROPANE-1, 1-DICARBOXAMIDE was obtained as an off white solid (15.0 g, 72percent yield).To a 100 ml reaction flask was added N- [3-fluoro-4 - [[6-methoxy-7-hydroxyquinolin-4-yl] oxy] phenyl] -N '- (4-fluorophenyl ) Cyclopropane-1, 1-dicarboxamide 5.4 g, 1.8 g of potassium carbonate, DMF 30ml, And heated to 85 ° C with stirring. After dissolving 2.1 g of N- (3-chloropropyl) morpholine in DMF, Was added dropwise to the above reaction solution for 6 h. The reaction solution cooled to room temperature was poured into 150 ml of water, extracted with dichloromethane (100 ml x 2), Dried over anhydrous sodium sulfate overnight. Filtration, vacuum distillation of dichloromethane, Column chromatography (mobile phase V / V: dichloromethane / methanol = 8/1) 4.8 g (70.9percent) of a pale yellow solid3A. Alternative Preparation of N3L reaction flask332. 3 g (lmol) of compound 6, 900 mL of DMF, 651.6 g (2 mol) of cesium carbonate, 336.8 g (1 mol) of compound 8, 16.1 g (0.05 mol) of TBAB, 60-70 ° C, After 8 h HPLC detection, Raw material reaction is complete, The reaction was stopped, After the system had cooled down to room temperature, 100 mL of water and 100 mL of isopropyl acetate were added. The layers were separated and the aqueous layer was extracted with 4 x 800 mL of isopropyl acetate. The combined organic layers were dried, filtered and the filtrate was dried under reduced pressure to give a brown solid 1, and the crude product was recrystallized from an ethanol / acetone solution to give a white crystalline solid (512.6g, yield: 81.0percent, HPLC: 99percentTo a three-necked flask was added 60 ml of tetrahydrofuran, and 1 - [[3-fluoro-4 - [[6-methoxy-7 - [[3- (morpholin-4-yl) propyl] oxy] Quinolin-4-yl] oxy] phenyl] carbamoyl] cyclopropanecarboxylic acid, and 3 drops of N, N-dimethylformamide, 0 ~ 5 drop oxalyl chloride 1.4ml, drop Bi, 10 ~ 20 stirring reaction for 2 hours, the reaction solution stand. To the 250 ml three-necked flask was added 1.4 g of p-fluoroaniline, 2.0 ml of triethylamine and 40 ml of tetrahydrofuran, and the reaction solution was added dropwise at 0 to 5 ° C, and the reaction was carried out at room temperature for 2 hours. Filtered, the solvent was evaporated under reduced pressure, 100 ml of dichloromethane was added, After dissolving, the mixture was washed with 0.5 mol / L hydrochloric acid (50 ml x 2), saturated brine (50 ml x 2) and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (mobile phase V / V: dichloromethane / methanol = 8/1) to give 3.2 g (50.2percent) of a pale yellow solid.1-(2-Fluoro-4-aminophenyl)-6-morpholinylpropoxy-7-methoxy-quinoline (0.18 g, 0.4 mmol) and N-p-fluoroanilino-cyclopropanedicarboxylic acid pentafluorophenol ester (0.18 g, 0.4 mmol) was dissolved in acetonitrile (50 mL), and potassium carbonate (0.2 g, 1 mmol) was added. stir at reflux overnight. After the reaction solution is concentrated to dryness, water is added. extracted with ethyl acetate. the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. pass the column (EA/PE=2:1) to get a white solid N-p-fluorophenyl-N-3-fluoro-4-[6-methoxy-7-(3-morpholinyl)methoxyquinolin-4-]oxyphenylcyclopropane-1, 1-dimethylamide.

XL880 (GSK1363089, EXEL-2880) is an ATP-competitive inhibitor of MET and KDR with IC50 of 0.4 nM and 0.9 nM, respectively.

Molecular Weight:632.7
XLogP3:5.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:12
Exact Mass:632.24464114
Monoisotopic Mass:632.24464114
Topological Polar Surface Area:111
Heavy Atom Count:46
Complexity:1010
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes