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Pharmaceutical salt of novel EGRF (Epidermal Growth factor Receptor) kinase inhibitor as well as preparation method and application of pharmaceutical salt

An amino, ethyl technology, applied in the preparation of carboxylate, sulfonate, pharmaceutical formulations and other directions

Active Publication Date: 2018-02-06
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compound AZD9291 (also known as N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylind Indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide) is an oral, irreversible EGFR inhibitor, but its metabolite AZ5104 is also potent against wild-type EGFR inhibition

Method used

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  • Pharmaceutical salt of novel EGRF (Epidermal Growth factor Receptor) kinase inhibitor as well as preparation method and application of pharmaceutical salt
  • Pharmaceutical salt of novel EGRF (Epidermal Growth factor Receptor) kinase inhibitor as well as preparation method and application of pharmaceutical salt
  • Pharmaceutical salt of novel EGRF (Epidermal Growth factor Receptor) kinase inhibitor as well as preparation method and application of pharmaceutical salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9- Tetrahydropyrido[1,2-a]indol-10-yl)-pyrimidin-2-yl)amino)phenyl)acrylamide

[0023]

[0024] Step a Synthesis of 1-(4-bromobutyl)-1H-indole

[0025]

[0026] In a 100mL reaction flask, add NaH (60% content, 1.23g, 30.73mmol) and DMF (10mL) in sequence, stir at room temperature for 5min and cool to 0-4°C, slowly add 10mL of dissolved indole (3g, 25.61mmol) DMF solution, after the addition was completed, raised to room temperature and reacted for 20 minutes to obtain an indole activation solution.

[0027] Another 250mL reaction flask was taken, and 1,4-dibromobutane (16.59g, 76.82mmol) and DMF (50mL) were added. Slowly add the indole activation solution prepared above dropwise at 0-4°C, and react at room temperature for 0.5 h after the drop is complete. After the reaction, quenched by adding water (100 mL), extracted with ethyl acetate, combined the ethyl acetate layers, dried over...

Embodiment 2

[0058] Example 2: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9- Tetrahydropyrido[1,2-a]indol-10-yl)-pyrimidin-2-yl)amino)phenyl)acrylamide methanesulfonate

[0059] Weigh compound (I) (148.5mg, 0.28mmol) and dissolve it in 1.49mL of 95% acetone. The solid dissolves at 55°C. Dilute methanesulfonic acid (29.11mg, 0.30mmol) with 1mL of acetone. The acetone solution of sulfonic acid was added to the acetone solution of the above compound (I), reacted for 2 hours, filtered, washed with acetone, and dried under vacuum at room temperature to obtain 155 mg of mesylate.

[0060] 1 H NMR (500MHz, DMSO-d 6 ):δ9.56(s,1H,disappear after heavy water exchange),9.20(s,1H,disappear after heavy water exchange),8.50(s,1H,),8.36(d,1H),8.09(d,1H), 7.91(s,1H,disappeared after heavy water exchange),7.43(d,1H),7.16(t,1H),7.12(t,1H),7.05(d,1H),6.97(s,1H,),6.63( dd,1H,),6.29(dd,1H),5.78(d,1H),4.11(t,2H),3.90(s,3H),3.33-3.31(m,2H),3.26-3.21(m,4H ), 2.81(s,6H), 2.62(s,3H), 2...

Embodiment 3

[0062] Example 3: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9- Tetrahydropyrido[1,2-a]indol-10-yl)-pyrimidin-2-yl)amino)phenyl)acrylamide maleate

[0063] Weigh compound (I) (148.5mg, 0.28mmol) and dissolve in 8.25mL isopropanol, dissolve clear maleic acid (35.16mg, 0.30mmol) with 2mL isopropanol, and dissolve maleic acid in isopropanol at room temperature The solution was added to the above-mentioned compound (I) in isopropanol, reacted for 2 hours, filtered, washed with isopropanol, and dried under vacuum at room temperature to obtain 100 mg of maleate.

[0064] 1 H NMR (500MHz, DMSO-d 6 ): δ9.64(s,1H),9.13(s,1H),8.47(s,1H),8.36(d,1H),8.10(d,1H),7.97(s,1H),7.45(d, 1H),7.16(t,1H),7.12(t,1H),7.05(d,1H),6.98(s,1H),6.57(dd,10.2Hz,1H),6.31(dd,1H),6.09( s,2H),5.81(d,1H),4.12(t,2H),3.90(s,3H),3.29-3.18(m,6H),2.80(s,6H),2.61(s,3H),2.03 -2.02(m,2H),1.84-1.82(m,2H).

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Abstract

The invention relates to pharmaceutical salt of a novel EGRF (Epidermal Growth factor Receptor) kinase inhibitor. Specifically, the invention relates to pharmaceutical salt of N-(2-(2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyridine[1,2-a]indole-10-yl)-pyrimidine-2-yl)amino)phenyl) allyl-acylamide and preparation method; the pharmaceutical salt can be used for preparing a medicine which is used for treating and / or preventing tumors and has drug resistance.

Description

technical field [0001] The invention relates to a novel medicinal salt of an EGFR kinase inhibitor and a preparation method thereof. In particular, the present invention relates to N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8 , A pharmaceutically acceptable salt of 9-tetrahydropyrido[1,2-a]indol-10-yl)-pyrimidin-2-yl)amino)phenyl)acrylamide and its preparation method and use. Background technique [0002] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase member of the erbB receptor family. Homodimerization and / or heterodimerization of the erbB receptor leads to phosphorylation of key tyrosine residues in the intracellular domain, stimulating many intracellular signaling pathways involved in cell proliferation and survival. Dysregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many cancers, such as lung, head and neck, and b...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07C309/04C07C303/32C07C51/41C07C57/145C07C59/08C07C59/265A61K31/506A61P35/00
CPCC07B2200/07C07D471/04
Inventor 赵立文符伟张晓平吴伟杰刘子宁金建淋
Owner NANJING SANHOME PHARMACEUTICAL CO LTD