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Urea-substituted aromatic ring dioxane-quinazoline or quinoline compound, composition and application thereof

A technology of compounds and substituents, which can be used in drug combinations, medical preparations containing active ingredients, organic chemistry, etc., and can solve problems such as unsuccessful marketing

Active Publication Date: 2021-04-06
BEIJING SCITECH MQ PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Currently, there are some ongoing studies on CSF1R inhibitors, but no successful marketed drugs

Method used

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  • Urea-substituted aromatic ring dioxane-quinazoline or quinoline compound, composition and application thereof
  • Urea-substituted aromatic ring dioxane-quinazoline or quinoline compound, composition and application thereof
  • Urea-substituted aromatic ring dioxane-quinazoline or quinoline compound, composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0095] Preparation of Intermediate 3.

[0096]

[0097] Step 1) A solution of 3-methoxyquinone (25.3g, 180mmol), potassium carbonate (104.5g, 756mmol), and 1,2-dibromoethane (74.4g, 396mmol) in DMF (100mL) Heated the reaction in a nitrogen system at 60°C for 6 hours. Quenched with water and extracted with ethyl acetate; the organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to give a dark gray oil: 5-methoxy -2,3-dihydrobenzo[b][1,4]dioxane (25.4g, 153mmol, yield 85%);

[0098] Step 2) under the ice-water bath condition of nitrogen atmosphere, to containing AlCl 3 (12.0g, 90mmol) in nitromethane (200mL) was slowly added dropwise acetyl chloride (5.57mL, 78mmol). Then slowly added dropwise 5-methoxy-2,3-dihydrobenzo[b][1, 4] Nitromethane (100mL) solution of dioxane (10.0g, 60mmol). The reaction was stirred at room temperature for 5 hours, and quenched by adding 1N hydrogen chloride solution. The org...

Embodiment 1

[0104] Example 1. 1-(1-(4-fluorophenyl)ethyl)-3-(4-((5-(3-morpholinopropyl)-2,3-dihydro-[1,4] Preparation of dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

[0105]

[0106] Step 1): Under ice-water bath conditions, add phenyl chloroformate and pyridine respectively to the DMF solution of 1-(4-fluorophenyl)ethyl-1-amine, stir at room temperature for 8 hours, the product (1-(4 -Fluorophenyl) ethyl) phenyl carbamate was directly used in the next step, MS: 260 [M+H] +

[0107] Step 2): Add 4-aminophenol to the reaction solution obtained in step 1), heat the reaction at 50°C for two hours, cool, add water to quench, extract with ethyl acetate, wash with saturated brine, dry the organic phase, and concentrate to obtain a gray color The solid product 1-(1-(4-fluorophenyl)ethyl)-3-(4-hydroxyphenyl)urea was used directly in the next step;

[0108] Step 3): The product obtained in step 2), 10-chloro-5-(3-morpholine propoxy)-2,3-dihydro-[1,4]dioxane[2,3-f ] quinazoline (intermedi...

Embodiment 2

[0110] Example 2. 1-(1-(4-fluorophenyl)ethyl)-3-(2-methyl-4-((5-(3-morpholinopropyl)-2,3-dihydro- [1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

[0111]

[0112] Operated with Example 1, the 4-aminophenol in step 2) was replaced by 4-amino-3-methylphenol to react to obtain a white solid product; 1 H NMR (300MHz, DMSO-d 6 )δ8.40(s,1H),7.84(d,J=6.0Hz,1H),7.70(s,1H),7.42-7.37(m,2H),7.18(t,J=9.0Hz,2H), 7.07(d,J=6.0Hz,1H),7.01-6.99(m,2H),6.92(d,J=9.0Hz,1H),4.85-4.80(m,1H),4.43-4.38(m,4H) ,4.20(br,2H),3.58(br,4H),2.45-2.38(m,6H),2.19(s,3H),1.96(br,2H),1.39(d,J=6.0Hz,3H). MS:618[M+H] + .

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Abstract

The present invention relates to a new class of compounds, compositions and applications as VEGFR-2 and CSF1R inhibitors. Specifically, the present invention provides a class of compounds (shown as formula (1)) or isomers, solvates, hydrates, pharmaceutically acceptable salts, pro- Medicines, and pharmaceutical compositions comprising the compounds. The present invention also discloses the application of the compound or the pharmaceutical composition of the present invention in preparing a medicine for treating autoimmune diseases, tumors, Alzheimer's disease and other diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of urea-substituted aromatic ring dioxane-quinazoline or quinoline compounds, their isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs , and pharmaceutical compositions thereof and their use in the treatment of autoimmune diseases, tumors and Alzheimer's disease associated with vascular endothelial growth factor receptor 2 (VEGFR-2) and / or colony stimulating factor 1 receptor (CSF1R) Application in pharmaceutical preparation. Background technique [0002] Protein kinases (PKs) are enzymes that catalyze the phosphorylation process of proteins. So far, more than 400 protein kinases have been discovered. As a subfamily of protein kinases, tyrosine kinases (RTKs) play important roles in cell signal transduction and are involved in tumorigenesis processes, including cell proliferation, survival, angiogenesis, invasion and metastasis. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/056A61P35/00A61P35/02A61P1/00A61P25/28A61P27/02A61P17/06A61P29/00A61P19/02A61P9/10A61P11/00A61P1/16A61K31/519A61K31/436A61K31/5377A61K31/541A61K31/4545A61K31/496
CPCA61P1/00A61P1/16A61P9/10A61P11/00A61P17/06A61P19/02A61P25/28A61P27/02A61P29/00A61P35/00A61P35/02C07D491/056A61K31/436A61K31/4545A61K31/4741A61K31/496A61K31/519A61K31/5377A61K31/541A61P37/00
Inventor 张强于善楠孙月明郑南桥杨磊夫
Owner BEIJING SCITECH MQ PHARMA LTD
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