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Phosphorus containing quinazoline compounds and methods of use

A kind of technology of compound and solvate, applied in the field of new quinazoline derivatives

Active Publication Date: 2012-10-03
JIANGSU KANION PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although several inhibitors of EGFR and ErbB2 signaling pathways have shown clinical efficacy in cancer therapy and several molecules have been approved by the FDA, there is still a need for better treatments for cancer due to the prevalence and complexity of cancer, such as Small molecule drugs with better pharmacological properties and / or lower toxicity

Method used

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  • Phosphorus containing quinazoline compounds and methods of use
  • Phosphorus containing quinazoline compounds and methods of use
  • Phosphorus containing quinazoline compounds and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0283]

[0284] N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((4-methyl-1,4-azaphosphin-1-yl)methyl) furan-2-yl)quinazolin-4-amine

[0285] Step A: 1-Benzyl-4-methyl-1,4-azaphosphine-4-oxide (Compound 1.1)

[0286] To a vigorously stirred solution of methyl dichlorophosphoric acid (6.65 g, 50 mmol) in THF (100 mL) was added vinylmagnesium chloride (1.6 M in THF, 66 mL, 105 mmol) dropwise over a period of 30 minutes at -78 °C. After the addition was complete, the reaction mixture was warmed to 0° C. over 1 hour, and benzylamine (6.43 g, 60 mmol) and methanol (100 mL) were added thereto. The reaction mixture was then refluxed for 36 hours. After cooling to room temperature, the reaction mixture was poured into a separatory funnel containing saturated aqueous ammonium chloride (100 mL), ethyl acetate (200 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted twice with dichloromethane (100 mL). The combined organic layer and extract w...

Embodiment 2

[0302]

[0303] 6-(5-((2-(Dimethylphosphino)ethylamino)methyl)furan-2-yl)-N-(4-(3-fluorobenzyloxy)-3-chlorobenzene base) quinazolin-4-amine

[0304] Step A: N-Benzyl-2-(dimethylphosphono)ethylamine (Compound 2.1)

[0305] To a vigorously stirred solution of dimethylphosphonyl chloride (6.65 g, 50 mmol) in THF (100 mL) was added vinylmagnesium chloride (1.6 M in THF, 33 mL, 52.5 mmol) dropwise over a period of 30 minutes at -78 °C . After the addition was complete, the reaction mixture was warmed to 0° C. over 1 hour, and benzylamine (6.43 g, 60 mmol) and methanol (100 mL) were added thereto. The reaction mixture was then refluxed for 36 hours. After cooling to room temperature, the solvent was removed and the residue was poured into a separating funnel containing ethyl acetate (200 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted twice with dichloromethane (100 mL). The combined organic layer and extract were dried over anhydr...

Embodiment 3

[0312]

[0313] 6-(5-(((dimethylphosphono)methylamino)methyl)furan-2-yl)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl) Quinazolin-4-amine

[0314] 5-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2-aldehyde (compound 1.7) and (dimethylphosphine Acyl)methylamine (Preparation: Maier, Ludwig Phosphorus, Sulfur and Silicon and the Related Elements, 53(1-4), 43-67; 1990) was suspended in dichloromethane (20 mL). Acetic acid (3 drops) and sodium triacetoxyborohydride (2 eq.) were then added sequentially at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N aqueous NaOH and extracted with dichloromethane. The combined organic layer and extract were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 20% methanol in dichloromethane to afford the desired product as a yellow crystalline solid.

[0315] ...

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Abstract

Disclosed are novel quinazoline derivatives containing phosphorus substitutions and methods for the treatment of hyperproliferative diseases (e.g. cancer) using the compounds. These compounds are type I receptor protein kinase inhibitors useful in treating disorders related to abnormal protein kinase activities such as cancer and inflammation in mammals. Also disclosed are pharmaceutical compositions containing the compounds, methods for the preparation of the compounds and their pharmaceutically acceptable salts.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 61 / 222,551, filed July 2, 2009, the disclosure of which is incorporated herein by reference in its entirety. field of invention [0003] The present invention relates to novel quinazoline derivatives comprising phosphorus substitutions as inhibitors of type I receptor protein kinases. These inhibitors are useful in the treatment of diseases associated with abnormal protein kinase activity (eg, cancer and inflammation) in mammals. The present invention relates to pharmaceutical compositions containing these inhibitors, processes for the preparation of these inhibitors and pharmaceutically acceptable salts thereof. Background of the invention [0004] The type I receptor tyrosine kinase family consists of four closely related receptors: ErbB1 (EFGR or HER1), ErbB2 (HER2), ErbB3 (HER) and ErbB4 (HER4). These receptors are transmembrane glyc...

Claims

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Application Information

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IPC IPC(8): A01N43/54A61K31/517
CPCC07F9/65128C07F9/65586C07F9/65685C07F9/657181A61P35/00A61P43/00C07F9/6584C07D405/04C07D239/74A61K31/517
Inventor 沈旺张爱民范俊发郑小琳
Owner JIANGSU KANION PHARMA CO LTD
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