Unlock instant, AI-driven research and patent intelligence for your innovation.

An acyl-substituted oxazinoquinazoline compound, its preparation method and its application

A compound, methyl technology, applied in the field of medicine, can solve problems such as narrow therapeutic window, unsatisfactory use effect, and reduced curative effect

Active Publication Date: 2020-12-25
BEIJING SCITECH MQ PHARMA LTD
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of inhibitor has inhibitory effects on wild-type and activating mutant EGFR at the same time, and has achieved great clinical success, but the drug resistance of recipient patients after taking it for a period of time, especially the drug resistance caused by the T790M mutation Sex reduces or loses efficacy
The second-generation EGFR inhibitor afatinib (Afatinib) is an irreversible inhibitor that contains a Michael receptor that can covalently bind to the cysteine ​​residue (Cys797) located at the entrance of the ATP binding pocket. The inhibitor shows strong activity against both T790M mutant EGFR kinase and wild-type EGFR kinase, and its inhibitory activity against T790M mutant EGFR kinase is higher than that of wild-type EGFR kinase, which makes the therapeutic window of the drug in clinical application narrower , the effect is not ideal (Camidge, D.R., et.al. (2014) Acquired resistance to TKIs in solid tumors: learning from lung cancer. Nature Reviews Clinical Oncology. 11, 473.)

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • An acyl-substituted oxazinoquinazoline compound, its preparation method and its application
  • An acyl-substituted oxazinoquinazoline compound, its preparation method and its application
  • An acyl-substituted oxazinoquinazoline compound, its preparation method and its application

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0163] The intermediates involved in the compounds of the present invention can be prepared by the following methods, but are not limited to the following methods. The synthesis of some intermediates of the present invention can refer to the method of patent CN104530063. For simple replacement of some functional groups, those skilled in the art can make corresponding adjustments to obtain corresponding intermediates according to the knowledge in the field of chemical synthesis. The following invention provides the preparation route of the intermediates, the intermediates involved in the compounds of the present invention can be prepared by the following schemes, but not limited to the following schemes.

[0164] The synthesis of the intermediate compound shown in formula VIII

[0165] Intermediate N-(3-bromophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1)

[0166]

[0167] Step 1) Preparation of 5-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one (II)

...

Embodiment 1

[0232] 1-(10-((3-bromophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)propane- Preparation of 2-en-1-one

[0233]

[0234] N-(3-bromophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1) (178mg, 0.5mmol) was dissolved in tetrahydrofuran, acryloyl chloride (45.3mg, 0.5mmol) was added, stirred at room temperature until the reaction was completed, quenched with potassium carbonate aqueous solution, extracted with ethyl acetate, concentrated organic phase and purified by silica gel column chromatography to obtain off-white 164 mg solid, 80% yield. 1 H NMR (500MHz, DMSO-d 6 )δ10.91(s,1H),8.82(s,1H),8.18(s,1H),7.95-7.90(m,1H),7.68-7.65(m,1H),7.56(dd,J=8.0, 0.9Hz, 1H), 7.52-7.45(m, 2H), 6.78-6.81(m, 1H), 6.35-6.30(m, 1H), 5.95-5.91(m, 1H), 4.71(t, J=4.5Hz ,2H),4.10(t,J=4.5Hz,2H); 13 C NMR (125MHz, DMSO) δ164.73, 159.84, 151.01, 144.14, 138.83, 133.14, 131.11, 130.22, 129.97, 129.30, 128.50, 125.08, 124.18, 121.67, 114.41, 090.070, 16; z 411.0...

Embodiment 2-82

[0236]

[0237] With reference to the preparation method of Example 1, its operation is exactly the same, and the embodiment is that R in the formula VIII with the same molar equivalent 1 X is an intermediate substituent in the table below to replace N-(3-bromophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline-10 -Amine (VIII-1), the compound of concrete implementation is shown in the table below:

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

Provided are an acyl-substituted oxazino-quinazoline compound, a preparation method therefor, and uses thereof. More particularly provided is a compound shown in formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt, a prodrug thereof, a preparation method therefor, and uses thereof in preparing a drug acting as a kinase inhibitor. Said compound has a good inhibitory activity on mutant EGFR kinases and a moderate inhibitory activity on wild-type EGFR kinases. (I)

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to an acyl-substituted oxazinoquinazoline compound, a preparation method and an application thereof. Background technique [0002] Protein kinase is an important signal messenger for cell life activities, which can catalyze the transfer of the γ-phosphate group at the end of ATP to the hydroxyl receptor in the substrate amino acid residue (serine, threonine, tyrosine), thereby activating the target Protein (Johnson L.N., and Lewis R.J., (2001) Structural basis for control by phosphorylation. Cheminform. 101, 2209.). Protein kinases are involved in numerous physiological processes, including cell proliferation, survival, apoptosis, metabolism, transcription, and differentiation (Adams J.A., (2001) Kinetic and catalytic mechanisms of protein kinases. Chemical reviews. 101, 2271.). Among the existing drug targets in the human body, members of the protein kinase family account for up to...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04A61K31/5383A61P35/00A61P37/00A61P27/02A61P17/06A61P17/00A61P17/14A61P19/02A61P1/00A61P9/10A61P35/02A61P11/00A61P1/16
CPCC07D498/04A61K31/5383A61P1/00A61P1/16A61P9/10A61P11/00A61P17/00A61P17/06A61P17/14A61P19/02A61P27/02A61P35/00A61P35/02A61P37/00
Inventor 张强于善楠王中祥冯守业郑南桥杨海龙杨磊夫张宏波周利凯
Owner BEIJING SCITECH MQ PHARMA LTD