PD 168393

PD168393 is an potent, cell-permeable, irreversible EGFR inhibitor with IC50 of 0.70 nM, irreversibly alkylate Cys-773, inactive against insulin, PDGFR, FGFR and PKC. target: EGFRIC 50: 0.7 nM [1](1) PD 168393 inhibite EGFr autophosphorylation in A431 human epidermoid carcinoma cells with >9-fold greater potency than PD 174265.[1](2) PD 168393 decrease the production of TNF-α and phosphrylation of ERK1/2 and p38 induced by LPS in cardiomyocytes.[2](3) PD168393 completely inhibits AKT and

PD 168393 is a member of the class of quinazolines carrying bromoanilino and acrylamido substituents at positions 4 and 6 respectively. It has a role as an epidermal growth factor receptor antagonist. It is a member of quinazolines, a member of acrylamides, a substituted aniline, a member of bromobenzenes and a secondary carboxamide.|PD-168393 is an epidermal growth factor receptor inhibitor.

To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (2.0 g, 6.35 mmol) in dry DMF (20 ML) under N2 was added acrylic acid (12.7 mmol, 0.87 mL). The resulting solution was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (7.62 mmol, 1.46 g) was added. The reaction was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stirred for a further 2 hours, after which additional acrylic acid (0.30 mL) and EDCI.HCl (0.30 g) were added. After a further 2 hours, the reaction was complete by tlc, solvent was removed under reduced pressure, and the resulting residue diluted with saturated NaHCO3 and repeatedly extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatography on grade III alumina eluding with EtOAc/MeOH (95:5) followed by recrystallization from EtOAc/hexane gave a spongy white solid, which upon several hours under high vacuum gave N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.06 g, 45percent) as a cream powder, mp 258-261° C. 1H NMR [(CD3)2SO, 200 MHz]: δ 10.51 (s, 1H, CONH), 9.93 (s, 1H, NH), 8.83 (br s, 1H, H-5), 8.59 (s, 1H, H-2), 8.18 (br s, 1H, H-2'), 7.94-7.78 (m, 3H, H-6', 8, 5'), 7.40-7.27 (m, 2H, H-7, 4'), 6.54 (dd, J =9.8 Hz, J =17.0 Hz, 1H, CH2CHCO), 6.36 (dd, J =2.1 Hz, J =16.9 Hz, 1H, CH2CHCO), 5.85 (dd, J =2.0 Hz, J =9.7 Hz, 1H, CE2CHCO). Mass spectrum (CI): 371 (95, 81BrMH+), 370 (53, 81BrM+), 369 (100, 79BrMH+), 368 (33, 79BrM+). Analysis calculated for C17H13BrN4O requires: C, 55.30; H, 3.55; N, 15.17percent. Found: C, 55.19; H, 3.34; N, 14.88percent.EXAMPLE 3 EXAMPLE 6 To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (2.0 g, 6.35 mmol) in dry DMF (20 ML) under N2 was added acrylic acid (12.7 mmol, 0.87 mL). The resulting solution was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (7.62 mmol, 1.46 g) was added. The reaction was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stirred for a further 2 hours, after which additional acrylic acid (0.30 mL) and EDCI.HCl (0.30 g) were added. After a further 2 hours, the reaction was complete by tlc, solvent was removed under reduced pressure, and the resulting residue diluted with saturated NaHCO3 and repeatedly extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatography on grade III alumina eluding with EtOAc/MeOH (95:5) followed by recrystallization from EtOAc/hexane gave a spongy white solid, which upon several hours under high vacuum gave N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.06 g, 45percent) as a cream powder, mp 258-261° C. 1H NMR [(CD3)2SO, 200 MHz]: δ 10.51 (s, 1H, CONH), 9.93 (s, 1H, NH), 8.83 (br s, 1H, H-5), 8.59 (s, 1H, H-2), 8.18 (br s, 1H, H-2'), 7.94-7.78 (m, 3H, H-6', 8, 5'), 7.40-7.27 (m, 2H, H-7, 4'), 6.54 (dd, J =9.8 Hz, J =17.0 Hz, 1H, CH2CHCO), 6.36 (dd, J =2.1 Hz, J =16.9 Hz, 1H, CH2CHCO), 5.85 (dd, J =2.0 Hz, J =9.7 Hz, 1H, CE2CHCO). Mass spectrum (CI): 371 (95, 81BrMH+), 370 (53, 81BrM+), 369 (100, 79BrMH+), 368 (33, 79BrM+). Analysis calculated for C17H13BrN4O requires: C, 55.30; H, 3.55; N, 15.17percent. Found: C, 55.19; H, 3.34; N, 14.88percent.EXAMPLE 3 EXAMPLE 6 A stirred solution of N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.78 g, 4.82 mmol), morpholine (excess, 4.0 mL) and p-toluenesulfonic acid (catalytic) in THF (50 mL) was heated at 50 C. for 4 hours before being concentrated under reduced pressure, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and chromatographed on silica gel eluting with MeOH/CH2Cl2/EtOAc (15:40:45) to give N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]-3-morpholino-propylamide (1.86 g, 78%) as a cream powder, mp (EtOAc) 184-186 C. 1H NMR [(CD3)2SO]: delta 10.37 (s, 1H, CONH), 9.91 (s, 1H, NH), 8.72 (d, J=1.9 Hz, 1H, H-5), 8.58 (s, 1H, H-2), 8.17 (t, J=2.1 Hz, 1H, H-2'), 7.86 (m, 2H, H-7, 6'), 7.78 (d, J=8.9 Hz, 1H, H-8), 7.35 (t, J=8.0 Hz, 1H, H-5'), 7.29 (dt, Jt=1.2 Hz, Jd=8.0 Hz, 1H, H-4'), 3.40 (t, J=4.6 Hz, 4H, morpholino methylene), 2.69 (t, J=6.6 Hz, 2H, NCH2CH2CONH), 2.58 (t, J=6.6 Hz, 2H, NCH2CH2CONH), 2.44 (br s, 4H, morpholino methylene). 13C NMR: delta 170.24, 157.18, 152.86, 146.48, 141.13, 136.87, 130.21, 128.39, 127.01, 125.74, 124.21, 121.03, 120.79, 115.40, 111.46, 66.09 (2), 54.04, 53.00 (2), 33.66. Analysis calculated for C21H22BrN52 requires: C, 55.3; H, 4.9; N, 15.3%. Found: C, 55.1; H, 5.2; N, 15.2%.To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (2.0 g, 6.35 mmol) in dry DMF (20 ML) under N2 was added acrylic acid (12.7 mmol, 0.87 mL). The resulting solution was cooled to 0 C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (7.62 mmol, 1.46 g) was added. The reaction was stirred at 0 C. for 15 minutes and then allowed to warm to room temperature and stirred for a further 2 hours, after which additional acrylic acid (0.30 mL) and EDCI.HCl (0.30 g) were added. After a further 2 hours, the reaction was complete by tlc, solvent was removed under reduced pressure, and the resulting residue diluted with saturated NaHCO3 and repeatedly extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatography on grade III alumina eluding with EtOAc/MeOH (95:5) followed by recrystallization from EtOAc/hexane gave a spongy white solid, which upon several hours under high vacuum gave N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.06 g, 45%) as a cream powder, mp 258-261 C. 1H NMR [(CD3)2SO, 200 MHz]: delta 10.51 (s, 1H, CONH), 9.93 (s, 1H, NH), 8.83 (br s, 1H, H-5), 8.59 (s, 1H, H-2), 8.18 (br s, 1H, H-2'), 7.94-7.78 (m, 3H, H-6', 8, 5'), 7.40-7.27 (m, 2H, H-7, 4'), 6.54 (dd, J =9.8 Hz, J =17.0 Hz, 1H, CH2CHCO), 6.36 (dd, J =2.1 Hz, J =16.9 Hz, 1H, CH2CHCO), 5.85 (dd, J =2.0 Hz, J =9.7 Hz, 1H, CE2CHCO). Mass spectrum (CI): 371 (95, 81BrMH+), 370 (53, 81BrM+), 369 (100, 79BrMH+), 368 (33, 79BrM+). Analysis calculated for C17H13BrN4O requires: C, 55.30; H, 3.55; N, 15.17%. Found: C, 55.19; H, 3.34; N, 14.88%.N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2-propenamide A solution of 2.0 g of N-(3-bromophenyl)-4, 6-quinazolindiamine in 10 ml of pyridine was cooled in an ice bath and a solution of 0.61 ml of acryoyl chloride in 30 ml of ether was added dropwise at 0 C. After stirring at room temperature for 3.5 hours, the solvents were removed at reduced pressure. The residue was purified by chromatography to give 0.2 g of N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2-propenamide A solution of 2.0 g of N-(3-bromophenyl)-4, 6-quinazolindiamine in 10 ml of pyridine was cooled in an ice bath and a solution of 0.61 ml of acryoyl chloride in 30 ml of ether was added dropwise at 0C. After stirring at room temperature for 3.5 hours, the solvents were removed at reduced pressure. The residue was purified by chromatography to give 0.2 g of 4-(3-bromo phenyl amine)-6-(vinyl amide) quinazoline (II), from (13) To a solution of 4-(3-bromo phenyl amine)-6-(3-methylsulfono propionyl amide) quinazoline (13) (0.090g, 0.1 mmol) in DMF (1.5 mL), was added potassium tert-butoxide (0.035 g, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, whereupon the reaction was completed (TLC/HPLC). A darkening and a slight exotherm (22 to 24 C) was observed initially upon the base addition. The mixture was partitioned between ethyl acetate (10 mL) and aqueous sodium chloride (10 mL, 20%). The layers were separated; the organic layer extracted to neutrality with aqueous sodium chloride (3x10 mL, 20%), dried over anhydrous magnesium sulfate (1.5 g) for at least one hour and filtered over a plug of silica gel (3 g). The plug was washed with a solution of ethyl acetate-10% methanol (20 mL-2 mL). The combined filtrates were concentrated under vacuum to a yellow solid (0.075 g) which was added to it ethyl ether (3 mL), stirred for one hour, filtered, washed with ethyl ether (3x0.5 mL) and dried under vacuum (60 C). The light yellow solid, 0.055 g (74.3%) was identical to the title compound (1); m.p. 288-290 C(dec.). TLC (dichloromethane-5% methanol) showed one single spot at Rf 0.40, identical to authentic; 1H NMR (300 MHz, DMSO-d6) 5.85 (d, Jcis=11Hz, 1H, C=CH geminal vinyl), 6.35 (d, Jtrans=15Hz, 1H, C=CH geminal vinyl), 6.54 (q, Jtrans=10Hz, Jcis=7Hz, 1H, C=CH-C=O- vicinal vinyl), 7.20-8.90 (m, 8H, Ar-H), 9.94 (s, 1H, NH amide), 10.55 (s, 1H, NH amine).4-(3-bromo phenyl amine)-6-(vinyl amide) quinazoline (II) from (12) To a solution of 4-(3-bromo phenyl amine)-6-(3-methylsulfoxido propionyl amide) quinazoline (12) (0.043g, 0.1 mmol) in DMF (2 mL), was added potassiumtert-butoxide (0.035 g, 0.3 mmol). The reaction mixture was stirred at ambient temperature for one hour, whereupon the reaction was completed (TLC/HPLC). A darkening, but no exotherm was observed initially upon the base addition. The reaction mixture was partitioned between ethyl acetate (10 mL) and aqueous sodium chloride (10 mL, 20%). The layers were separated, the organic layer extracted to neutrality with aqueous sodium chloride (3x10 mL, 20%), dried over anhydrous magnesium sulfate (1.5 g) for at least one hour, and filtered over a plug of silica gel (3 g). The plug was washed with a solution of ethyl acetate-10% methanol (20 mL-2 mL). The filtrates were concentrated under vacuum to a yellow solid (0.025 g). Ethyl ether (3 mL) was added, the mixture stirred for one hour, filtered, washed with ethyl ether (3x0.5 mL) and dried it under vacuum (60 C). The resulting light yellow solid, 0.020 g (55.0%) was identical to the title compound (II); m.p. 288-290 C(dec.).

Molecular Weight:369.2
XLogP3:3.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:368.02727
Monoisotopic Mass:368.02727
Topological Polar Surface Area:66.9
Heavy Atom Count:23
Complexity:433
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes