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Dioxane quinoline compound and preparation method and application thereof

A compound and hydrate technology, applied in the field of dioxane quinoline compounds, can solve problems such as side effects, limited access to drugs, drug resistance, etc.

Inactive Publication Date: 2019-08-23
BEIJING SCITECH MQ PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are few drugs currently on the market, and the access to them is limited, and problems such as drug resistance and side effects may occur in the use of marketed drugs

Method used

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  • Dioxane quinoline compound and preparation method and application thereof
  • Dioxane quinoline compound and preparation method and application thereof
  • Dioxane quinoline compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1. N-(4-fluorophenyl)-N-(4-((5-methoxy-2,3-dihydro-[1,4]dioxalo[2,3-f] Preparation of -quinolin-10-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide

[0124]

[0125] Step 1): Mix 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxano[2,3-f]quinoline (251 mg, 1 mmol) with p-nitrophenol (139mg, 1mmol) was placed in a reaction flask, added chlorobenzene, heated to reflux and stirred until the reaction was complete. Suction filtration after cooling, the obtained solid was washed with potassium carbonate aqueous solution to give light yellow solid (5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]diox Alkano[2,3-f]quinoline) 250 mg, yield 71%. MS:355[M+H] + .

[0126] Step 2): Put the product (250mg, 0.7mmol) obtained in step 1) into a reaction flask, add methanol and Raney nickel (250mg), stir under hydrogen atmosphere until the reaction is complete, filter and concentrate to obtain an off-white solid product (4-((5-methoxy-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy)...

Embodiment 2

[0128] Example 2. N-(3-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxano[2,3-f]-quinoline-10- Preparation of yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0129]

[0130] Step 1) 10-(2-fluoro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1,4]dioxano[2,3-f]-quinone Preparation of morphine

[0131] Referring to the operation of step 1) of Example 1, the same molar equivalent of 2-fluoro-4 nitrophenol can be used instead of p-nitrophenol. 1 HNMR (400MHz, DMSO-d 6 )δ8.67(d,J=5.0Hz,1H),8.44–8.27(m,1H),8.13–7.93(m,1H),7.19(s,1H),7.07(d,J=4.9Hz,1H ),6.98(t,J=8.7Hz,1H),4.31–4.18(m,2H),4.16–4.06(m,2H),3.95(s,3H); MS:373[M+H] + .

[0132] Step 2) 3-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy) Preparation of aniline

[0133] Reference Example 1 step 2) operation, with the same molar equivalent of 10-(2-fluoro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1,4]diox Alkano[2,3-f]quinoline instead of 5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]dioxa...

Embodiment 3

[0136] Example 3. N-(2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxalo[2,3-f]quinolin-10-yl Preparation of )oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0137] Step 1) 10-(3-fluoro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1,4]dioxano[2,3-f]quinoline preparation of

[0138] Referring to the operation of step 1) of Example 1, the same molar equivalent of 3-fluoro-4 nitrophenol can be used instead of p-nitrophenol. MS:373[M+H] + .

[0139] Step 2) 2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxano[2,3-f]quinolin-10-yl)oxy) Preparation of aniline

[0140] Reference Example 1 step 2) operation, with the same molar equivalent of 10-(3-fluoro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1,4]dioxin Alkano[2,3-f]quinoline instead of 5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]dioxano[2,3 -f] quinoline. 1 HNMR(400MHz,DMSO-d6)δ8.38(d,J=5.2Hz,1H),7.04(s,1H),6.98–6.91(m,1H),6.89–6.79(m,1H),6.78–6.67 (m,1H),6.37(d,J=5.2Hz,1H),5.14(s,2H),4.43–4.30(m,4H),3.91(s,3H); MS:343[M+...

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Abstract

The invention relates to a dioxane quinoline compound with a formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides preparation of the compound shown in the formula (I)and the pharmaceutically acceptable salt thereof and the application of the compound as a drug, wherein the drug is used as a tyrosine kinase (VEGFR-2 and c-MET) inhibitor for treating diseases related to tyrosine kinase.

Description

technical field [0001] The present invention relates to a dioxane quinoline compound, its pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug, and its preparation method and use. Background technique [0002] Receptor tyrosine kinases (RTKs) span the cell membrane and affect the transmembrane transmission of biochemical signals, which consist of an extracellular domain containing a ligand binding site, a single transmembrane domain, The intracellular domain consists of three parts. Ligand binding to the receptor stimulates receptor-associated tyrosine kinase activity that leads to phosphorylation of tyrosine residues on the receptor and other intracellular molecules, initiating a cascade leading to a variety of cellular responses Signal. The overexpression of tyrosine receptors activates downstream signal transduction pathways, which eventually leads to abnormal transformation and proliferation of cells, and promotes the occurrence and development of tum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/056A61P27/02A61P17/06A61P19/02A61P29/00A61P9/10A61P11/00A61P1/16A61P35/00A61P35/02A61K31/5377A61K31/436A61K31/4545A61K31/541A61K31/496
CPCC07D491/056A61P27/02A61P17/06A61P19/02A61P29/00A61P9/10A61P11/00A61P1/16A61P35/00A61P35/02
Inventor 张强于善楠王中祥冯守业孙月明刘彦生张宏波杨磊夫杨海龙周利凯郑南桥胡晨明徐占强
Owner BEIJING SCITECH MQ PHARMA LTD