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Compound used for discoidin domain receptor micro-molecule inhibitor, and its application

A small molecule inhibitor, domain technology, applied in the field of chemical medicine to avoid toxic side effects

Active Publication Date: 2014-08-06
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In fact, there is currently no discoid domain receptor inhibitor clinically used for the treatment of the above diseases

Method used

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  • Compound used for discoidin domain receptor micro-molecule inhibitor, and its application
  • Compound used for discoidin domain receptor micro-molecule inhibitor, and its application
  • Compound used for discoidin domain receptor micro-molecule inhibitor, and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] 4-Methyl-N-(3-((4-methylpiperazine-1-substituted)methyl)-5-(trifluoromethyl)phenyl)-3-(pyrazol[1,5-a ]pyrimidine-6-substituted ethynyl)benzamide (7-4090)

[0084] (4-Methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-(pyrazolo[1,5-a]pyrimidin-6-ylethynyl)benzamide)

[0085]

[0086] Step 1. Methyl3-ethynyl-4-methylbenzoate (Methyl3-ethynyl-4-methylbenzoate)

[0087]

[0088] Dissolve methyl 3-iodo-4-methylbenzoate (27.61 g, 100 mmol) in ethyl acetate (300 mL) and add Pd(PPh 3 ) 2 Cl 2 (0.70g, 1mmol), CuI (0.19g, 1mmol), and triethylamine (30.4g, 300mmol). Argon was replaced 3 times and stirred overnight at room temperature. The reaction solution was filtered with celite, and the filtrate was concentrated and subjected to column chromatography. A white solid (20.9 g, 85.0%) was obtained. The above product (19.7g, 80mmol) was dissolved in methanol (300mL), potassium carbonate (16.6g, 120mmol) was added with stirring, and stirred at room...

Embodiment 2

[0109] 4-Methyl-N-(3-(morpholinylmethyl)-5-(trifluoromethyl)phenyl)-3-(pyrazol[1,5-a]pyrimidine-6-substituted ethynyl)benzene Formamide (7-4086)

[0110] (4-Methyl-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-3-(pyrazolo[1,5-a]pyrimidin-6-ylethynyl)benzamide)

[0111]

[0112] The synthesis method is as in Example 1.

[0113] H NMR (400MHz, DMSO-d 6 ( d,J=2.0Hz,1H),8.20(s,1H),8.04(s,1H),7.98(dd,J=8.0,1.6Hz,1H),7.56(d,J=8.0Hz,1H), 7.38(s,1H),6.85(dd,J=2.0,0.4Hz,1H),3.60(t,J=4.4Hz,4H),3.56(s,2H),2.60(s,3H),2.40(t ,J=4.4Hz,4H).

[0114] LC-MS (ESI): m / z520[M+H] + ;518[M-H] - .

Embodiment 3

[0116] 4-Methyl-N-(3-(piperidine-1-substituted methyl)-5-(trifluoromethyl)phenyl)-3-(pyrazol[1,5-a]pyrimidine-6-substituted Ethynyl)benzamide (7-4144)

[0117] (4-Methyl-N-(3-(piperidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-3-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)benzamide)

[0118]

[0119] The synthesis method is as in Example 1.

[0120] 1 H NMR (400MHz, DMSO-d 6 ) δ10.58 (s, 1H), 9.58 (d, J=1.2Hz, 1H), 8.72 (d, J=2.0Hz, 1H), 8.34 (d, J=2.4Hz, 1H), 8.22 (d, J=1.2Hz,1H),8.19(s,1H),8.01(s,1H),7.97(dd,J=8.0,1.6Hz,1H),7.55(d,J=8.0Hz,1H),7.35( s,1H),6.85(d,J=2.0Hz,1H),3.51(s,2H),2.59(s,3H),2.35(brs,4H),1.52(quint,J=4.2Hz,4H), 1.42-1.38 (m, 2H).

[0121] LC-MS (ESI): m / z518[M+H] + ;516[M-H] - .

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Abstract

The invention discloses a compound having a structure represented by formula (I) and used for a discoidin domain receptor micro-molecule inhibitor, or its pharmaceutically acceptable salt or stereo isomer or prodrug molecule. The above compounds can effectively inhibit the activity of the discoidin domain receptor, and can be used for preparing drugs for preventing and treating inflammations, liver fibration, kidney fibration, lung fibration, skin scars or atherosclerosis.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to a compound used as a discoid domain receptor small molecule inhibitor and application thereof. Background technique [0002] Discoidin domain receptors (DDRs) are a subfamily of transmembrane receptor tyrosine protein kinases, including two subtypes DDR1 and DDR2. In the tyrosine kinase region, these two subtypes have 89% homology. Discoid domain receptors are structurally distinct from other receptor tyrosine kinases in that they have two extracellular discoid structures. DDR1 is mainly expressed in epithelial cells of lung, kidney, colon and brain, while DDR2 is mainly expressed in mesenchymal cells such as fibroblasts, myofibroblasts and smooth muscle cells of kidney, skin, lung, heart and connective tissue. Much evidence has shown that aberrant expression of discoid receptors is associated with various disease processes, such as inflammation, liver fibrosis...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61P29/00A61P1/16A61P13/12A61P11/00A61P17/02A61P9/10
CPCC07D487/04
Inventor 丁克高明山冯玉冰李伟华
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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