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Dioxanoquinazoline amine compound and preparation method thereof, and application of dioxanoquinazoline amine compound as epidermal growth factor receptor inhibitor

A compound and dioxane technology, applied in organic chemistry, drug combination, pharmaceutical formulation, etc., can solve the problem of limited survival time extension

Active Publication Date: 2016-08-10
BEIJING SCITECH MQ PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the existence of drug resistance, the prolongation of survival time of most advanced patients is still limited (Kobayashi, S.; Boggon, T.J.; Dayaram, T.; et al.N.Engl.J.Med.2005,352,786)

Method used

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  • Dioxanoquinazoline amine compound and preparation method thereof, and application of dioxanoquinazoline amine compound as epidermal growth factor receptor inhibitor
  • Dioxanoquinazoline amine compound and preparation method thereof, and application of dioxanoquinazoline amine compound as epidermal growth factor receptor inhibitor
  • Dioxanoquinazoline amine compound and preparation method thereof, and application of dioxanoquinazoline amine compound as epidermal growth factor receptor inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] N-(3-chloro-4-fluorophenyl)-5-(2-methoxyethoxy)-3-(methoxymethyl)-2,3-dihydro[1,4]dioxin Preparation of alkano[2,3-f]quinazolin-10-amine (I-1)

[0054] Step 1) Preparation of 2,3,4-trihydroxybenzoic acid methyl ester

[0055]

[0056] At room temperature, add 34 grams (200 mmol) of 2,3,4-trihydroxybenzoic acid and 40 grams (400 mmol) of potassium bicarbonate, and 300 mL of N,N-dimethylformamide into the reactor and stir slowly for 0.5 hours, then add 42 g ( 300 mmol) methyl iodide, reacted for 12 hours, poured into 1500 mL of water, filtered with suction, washed with water, and dried to obtain 35 g of white solid with a yield of 95%. 1 H NMR (400MHz, CDCl 3 )δ11.01(s,1H),7.38(d,J=8.8Hz,1H),6.53(d,J=8.8Hz,1H),5.80(s,1H),5.47(s,1H),3.94( s,3H).ESI-MS m / z:185[M+H] + .

[0057] Step 2) Preparation of 2,3,4-tribenzyloxymethylbenzoate

[0058]

[0059] Mix 18.5 grams (100 mmol) of methyl 2,3,4-trihydroxybenzoate, 42.0 grams (300 mmol) of potassium carbonate and 15...

Embodiment 2

[0094] N-(3-fluorophenyl)-5-(2-methoxyethoxy)-3-(methoxymethyl)-2,3-dihydro[1,4]dioxano[2 , 3-f] the preparation of quinazoline-10-amine (I-2)

[0095]

[0096] Steps 1) to 12) are the same as in Example 1;

[0097] 10-Chloro-5-(2-methoxyethyl)-3-(methoxymethyl)-2,3-dihydro[1,4]dioxane[2,3-f]quinazole Add morphine (100mg, 0.29mmol) into a 25mL round-bottomed flask, add 10mL of isopropanol and stir, add 3-fluoroaniline (38mg, 0.35mmol), heat to reflux for 2h, cool, filter the precipitated crystals and wash with a small amount of isopropanol The crystals were washed and dried to obtain 69 mg of white solid with a yield of 58%. Melting point: 231.6-232.2°C. 1 H NMR (500MHz, CD 3 OD+CDCl 3 )δ8.58(s,1H),7.63(dt,J=10.3,2.2Hz,1H),7.48–7.37(m,2H),7.11(s,1H),7.09–7.01(m,1H),4.83 (dd,J=11.4,2.2Hz,1H),4.55–4.50(m,1H),4.44(dd,J=11.4,7.5Hz,1H),4.38(t,J=4.4Hz,2H),3.88( dd,J=7.2,3.7Hz,2H),3.82(qd,J=10.7,4.9Hz,2H),3.47(d,J=1.5Hz,6H). 13 CNMR (125MHz, CD 3 OD+CDCl 3 ( d,J=9.1Hz),...

Embodiment 3

[0099] N-(3-chlorophenyl)-5-(2-methoxyethoxy)-3-(methoxymethyl)-2,3-dihydro[1,4]dioxano[2 ,3-f] the preparation of quinazoline-10-amine (I-3)

[0100]

[0101] Steps 1) to 12) are the same as in Example 1;

[0102] 10-Chloro-5-(2-methoxyethyl)-3-(methoxymethyl)-2,3-dihydro[1,4]dioxane[2,3-f]quinazole Add morphine (100mg, 0.29mmol) into a 25mL round-bottomed flask, add 10mL of isopropanol and stir, add 3-chloroaniline (44mg, 0.35mmol), heat to reflux for 2h, cool, filter the precipitated crystals and wash with a small amount of isopropanol The crystals were washed and dried to obtain 77 mg of white solid with a yield of 62%. Melting point: 233.3-234.7°C. 1 H NMR (500MHz, CD 3 OD+CDCl 3 )δ8.59(s,1H),7.82(s,1H),7.56(d,J=8.0Hz,1H),7.43(t,J=8.1Hz,1H),7.33(d,J=8.0Hz, 1H),7.14(s,1H),4.84(dd,J=11.3,1.7Hz,1H),4.54(d,J=5.0Hz,1H),4.45(dd,J=11.3,7.5Hz,1H), 4.40(t, J=4.3Hz, 2H), 3.92–3.87(m, 2H), 3.83(qd, J=10.8, 4.8Hz, 2H), 3.49(d, J=0.9Hz, 6H). 13 C NMR (125MHz, CD 3 OD+CDCl ...

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Abstract

The invention discloses 3-methoxymethyl-2,3-dihydro-[1,4]dioxano[2,3-f]quinazoline-10-amine compound and a preparation method thereof, and application of the compound as an epidermal growth factor receptor inhibitor for treating cancers, belonging to the field of biology. The compound is an N-substituted phenyl-5-substituted alkoxy-3-methoxymethyl-2,3-dihydro-[1,4]dioxano[2,3-f]quinazoline-10-amine compound as shown in a formula (I) which is described in the specification, or a pharmaceutically acceptable salt or a prodrug molecule thereof. In the formula (I), R<1> is selected from a group consisting of -H, C1-5 straight-chain or branched-chain alkyl groups, alkyloxy groups, alkyloxy-substituted C1-5 straight-chain or branched-chain alkyl groups, etc.; R<2> is selected from a group consisting of -H, halogen, aromatic alkyloxy groups, C1-3 alkyl groups, and C1-3 straight-chain or branched-chain alkoxy groups; and R<3> is selected from a group consisting of -H, halogen, C1-4 unsaturated alkyl groups, nitro groups, cyano groups and C1-3 straight-chain or branched-chain alkoxy groups. The compound provided by the invention can be applied to treatment or prevention a variety of cancers.

Description

technical field [0001] The present invention relates to N-substituted phenyl-5-substituted alkoxy-3-methoxymethyl-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline- 10-amine compounds and their preparation methods and applications. Specifically, N-substituted phenyl-5-substituted alkoxy-3-methoxymethyl-2,3-dihydro-[1,4]dioxane[2,3 -f] quinazoline-10-amine compounds, their preparation methods and their use as epidermal growth factor receptor inhibitors for treating cancer. Background technique [0002] Cancer is a malignant disease that seriously threatens human existence. According to statistics from the International Agency for Research on Cancer (IARC), there were 14.1 million new cancer patients and 8.2 million cancer-related deaths worldwide in 2012; compared with 12.7 million and 7.6 million in 2008; new cancer cases in my country 3.065 million, the death toll is about 2.5 million. In recent years, with the aging of the population and the increase of environmental pollution...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/056A61K31/519A61K31/5377A61P35/00A61P35/02
CPCC07D491/056
Inventor 盛望杨磊夫潘智勇
Owner BEIJING SCITECH MQ PHARMA LTD
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