2-Methoxy-N-[(2E)-3-[4-[[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]phenyl]amino]-6-quinazolinyl]-2-propen-1-yl]acetamide Chemical Properties

Boiling point:

687.3±55.0 °C(Predicted)

Density 

1.251

storage temp. 

Store at -20°C

solubility 

DMF: 3 mg/ml; DMF:PBS(pH 7.2)(1:1): 0.5 mg/ml; DMSO: 3 mg/ml; Ethanol: 2 mg/ml

form 

A crystalline solid

pka

13.95±0.46(Predicted)

color 

Light yellow to yellow

2-Methoxy-N-[(2E)-3-[4-[[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]phenyl]amino]-6-quinazolinyl]-2-propen-1-yl]acetamide Usage And Synthesis

Description

CP 724,714 is a selective inhibitor of HER2/ErbB2 with an IC₅₀ value of 10 nM. It demonstrates greater than 640-fold selectivity against EGFR, InsR, IRG-1R, PDGFR, VEGFR2, Abl, Src, and c-Met. CP 724,714 has been shown to inhibit the proliferation of ErbB2-amplified cells, including BT474 and SK-BR-3 with IC₅₀ values of 0.25 and 0.95 μM, respectively. It also demonstrates antitumor activity in various human tumor xenograft models. However, CP 724,714 was discontinued from clinical development due to hepatotoxicity caused by its ability to inhibit hepatic efflux transporters at low micromolar concentrations.

Uses

CP 724714 is a HER-2 tyrosine kinase inhibitor used in tumor treatments for HER2 positive solid tumors.

Definition

ChEBI: CP-724714 is a 2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide in which the double bond adopts a trans-configuration. It is a potent inhibitor of HER2/ErbB2 (IC50 = 10 nM) and exhibits anti-cancer activity. It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, an antineoplastic agent, an apoptosis inducer and a hepatotoxic agent.

Synthesis

Synthesis of (E)-2-methoxy-N-(3-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)allyl)-N-(3-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)quinazolin-6-yl)allyl)amide from 6-iodo-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)allyl)acetamide as raw material (CAS:537705-07-0) The general procedure for acetamide is as follows: 1. 2-Methyl-2-butene (0.59 mL, 5.60 mmol, 2.8 eq.) was added dropwise to a BH3?THF complex (1.0 M solution, 3.0 mL, 3.0 mmol, 1.5 eq.) cooled to 0-5°C over a period of 1 hour under nitrogen protection. The reaction mixture was stirred at this temperature for 30 min. 2. 2-Methoxy-propionamide acetate (255 mg, 2 mmol, 1.0 eq.) dissolved in dry THF (1 mL) was added to the reaction mixture over 15 minutes. The ice bath was removed and the reaction mixture was slowly warmed to room temperature over 20 min followed by heating at 35°C for 1 hr. 3. K2CO3 (0.55 g, 4 mmol, 2.0 eq.) was dissolved in degassed H2O (1.2 mL) and added dropwise to the reaction mixture over 30 min. Gas release was observed during dropwise addition. 4. 6-Iodo-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazoline (1.41 g, 3 mmol, 1.5 eq.) was added to the yellow suspension in three batches. PPh3 (21 mg, 0.08 mmol, 4 mol%) and Pd(OAc)2 (4.5 mg, 0.02 mmol, 1 mol%) were then added separately and the reaction mixture was heated to reflux (65-68°C). 5. After about 30 min, the reaction mixture changed to a yellow solution and the reaction progress was monitored by HPLC. after 18 h, the reaction mixture was cooled to room temperature. 6. Half-saturated NaCl solution (10 mL) and EtOAc (10 mL) were added, the organic phase was separated, washed with H2O (5 mL), and concentrated at 50°C and a pressure below 200 mbar. 7. Purification by silica gel column chromatography (EtOAc/MeOH = 9/1) afforded (E)-2-methoxy-N-(3-(4-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)allyl)acetamide as light yellow crystals (0.55 g, 59%). rf = 0.16 (EtOAc/ MeOH = 9/1). NMR data: 1H-NMR (CDCl3, 250 MHz): δ = 8.71 (s, 1H, H-2), 8.25 (d, J = 1.7 Hz, 1H, H-8), 7.90 (s, 1H, H-7), 7.82 (s, 1H, NH), 7.79 (s, 1H, H-5), 7.66 (d, J = 2.5 Hz, 1H, H-4'). 7.54 (dd, J1 = 8.7 Hz, J2 = 2.6 Hz, 1H, H-5'), 7.15-7.07 (m, 2H, H-5', H-6'), 6.91 (dt, J = 8.7 Hz, 1H, H-2'), 6.83 (bt, 1H, NH), 6.65 (dt, J = 15.9 Hz, 1H, H-9), 6.34 and 6.29 (dt, J1 = 15.9 Hz, J2 = 6.1 Hz, 1H, H-10), 4.14 (dt, J = 6.1 Hz, 2H, CH2OMe), 3.97 (s, 2H, CH2NH), 3.45 (s, 3H, OCH3), 2.53 (s, 3H, CH3), 2.29 (s, 3H, CH3). 13C-NMR (CDCl3, 75 MHz): δ = 169.76 (C=O), 157.90, 154.93, 152.367, 152.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16, 130.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65, 121.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57, 16.41. The analytes were analyzed by reversed-phase high performance liquid chromatography (HPLC) using a Symmetry Shield RP18 column, 75 x 4.6 mm, flow rate of 1.0 mL/min, detection wavelengths of 205/210/220/245 nm, temperature 25°C, injection volume of 10 μL, about 0.5% ACN/H2O solution, eluent B was ACN, eluent C was 0.01 mmol NH4OAc in H2O, pH = 6.0), gradient elution conditions: 0 min B = 30%, C = 70%; 20 min B = 85%, C = 15%. Under these conditions, the retention time (tR) of (E)-2-methoxy-N-(3-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)allyl)acetamide was 6.02 min.

in vivo

IC 50

ErbB2: 10 nM (IC₅₀)

References

[1] Patent: WO2004/56802, 2004, A1. Location in patent: Page 15-16
[2] Patent: US2005/192298, 2005, A1. Location in patent: Page/Page column 7