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Hydrochloride of pyrrolo-pyrazine compound and application of hydrochloride

A technology of hydrochloride and pyrrole, which is applied in the application field of pyrrolopyrazine compounds and drug preparation, and can solve problems such as disease recurrence

Active Publication Date: 2015-04-29
NANJING SANHOME PHARM RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The development and clinical use of imatinib has opened a new era of tumor molecular targeting, but long-term use of imatinib will cause drug resistance and lead to disease recurrence

Method used

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  • Hydrochloride of pyrrolo-pyrazine compound and application of hydrochloride
  • Hydrochloride of pyrrolo-pyrazine compound and application of hydrochloride
  • Hydrochloride of pyrrolo-pyrazine compound and application of hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] Example 1 Preparation of 3-ethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

[0125]

[0126] Step 1 Preparation of 3-iodo-4-methyl-N-[4-(4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

[0127] 4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline (2.27 g, 8.3 mmol), 3-iodo-4-methyl-benzoyl chloride ( 10mmol), 15ml tetrahydrofuran, 10ml triethylamine, stirred at room temperature for 4 hours. Add saturated NaHCO 3 Solution washing, ethyl acetate and water extraction, saturated NaCl solution washing, anhydrous NaCl 2 SO 4 After drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column to give the title compound as a yellow oil.

[0128] 1 H NMR (500MHz, CDCl 3 )δ:8.39(s,1H,N-H),8.29(s,1H,Ar-H),7.88(d,1H,Ar-H),7.86(s,1H,Ar-H),7.75(d,1H ,Ar-H),7.73(d,1H,Ar-H),7.28(d,1H,Ar-H),3.62(s,2H,PhCH 2 ),2.60(b,8H,4×-CH 2 ),2.47(s,3H,-CH 3 ),2.31(s,3H,-CH 3 )....

Embodiment 2

[0135] Example 2 3-((1H-pyrrolo[2,3-b]pyrazin-5-yl)ethynyl)-4-methyl-N-[4-((4-methylpiperazine-1- Base) methyl) -3-trifluoromethylphenyl] benzamide preparation

[0136]

[0137] Add the compound prepared in Example 1 (126mg, 0.3mmol), 5-bromo-1H-pyrrolo[2,3-b]pyrazine (59mg, 0.3mmol), Pd(PPh 3 ) 2 Cl 2 (63mg, 0.006mmol), CuI (18mg, 0.09mmol), 1mL Et 3N and 5mL DMF, under the protection of inert gas, stirred at 80°C for 8 hours. After the reaction was completed, extract with ethyl acetate and water, combine the organic layers, wash with saturated NaCl solution, anhydrous NaCl 2 SO 4 dry. Concentration under reduced pressure and the residue was purified by silica gel column to obtain the compound as an off-white solid.

[0138] 1 H NMR (500MHz, CDCl 3 )δ:8.91(br,1H,-NH),8.46(s,1H,Ar-H),8.02(d,1H,Ar-H),7.98(s,1H,Ar-H),7.87(s, 1H,Ar-H),7.85(s,-NH,1H),7.78-7.80(m,1H,Ar-H),7.69-7.70(d,1H,Ar-H),7.60-7.62(m,1H ,Ar-H),7.35(d,1H,Ar-H),6.72-6.73(m,1H,Ar-H),3.61(s,2H,-CH 2 ...

Embodiment 3

[0140] Example 3 3-((1H-pyrrolo[2,3-b]pyrazin-5-yl)ethynyl)-4-methyl-N-[4-((4-methylpiperazine-1- Base) methyl) -3-trifluoromethylphenyl] benzamide hydrochloride

[0141] Weigh 3-((1H-pyrrolo[2,3-b]pyrazin-5-yl)ethynyl)-4-methyl-N-[4-((4-methylpiperazin-1-yl )methyl)-3-trifluoromethylphenyl]benzamide (30mg) was dissolved in 5mL of methanol, and ethyl hydrogen chloride solution was added dropwise to a pH value of about 3, stirred at room temperature for 3h, and evaporated under reduced pressure to remove the volatile The material was dried in vacuo at 50 °C for 5 h to afford the title compound.

[0142] 1 H NMR (300MHz, DMSO-d 6 )δ:12.34(s,1H),10.61(s,1H),10.25(b,1H),8.56(s,1H),8.26(s,2H),8.14(d,1H),7.96-8.01(m ,2H),7.73(d,1H),7.56(d,1H),6.67-6.69(m,1H),3.70(s,2H),3.37(m,4H),2.89-3.06(m,4H), 2.77(s,3H), 2.61(s,3H).

[0143] 1 H NMR (300MHz, DMSO-d 6 +D 2 O)δ:10.62(s,1H),8.57(s,1H),8.22(s,2H),8.07(d,1H),7.93-7.99(m,2H),7.74(d,1H),7.56( d,1H),6.71(d,1H),3.70(s,2H),3.38-...

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Abstract

The present invention relates to the field of chemical medicines, in particular to compounds as represented by formula I having BCR-ABL kinase inhibitory activity, or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and pharmaceutical composition containing the compounds, and application of the compounds or compositions in drug preparation. The compounds of the present invention have strong inhibitory effect on BCR-ABL kinase, and can be used to treat diseases such as tumors.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a pyrrolopyrazine compound with BCR-ABL kinase inhibitory activity, a pharmaceutical composition containing the compound, and an application of the compound or the composition in drug preparation. Background technique [0002] Protein tyrosine kinases (PTKs) are a class of kinases that can catalyze the transfer of γ-phosphate on ATP to protein tyrosine residues. A protein enzyme system that acts on a functional protein. Protein tyrosine kinases (PTKs) play a very important role in intracellular signal transduction pathways, regulating a series of physiological and biochemical processes such as cell growth, differentiation, and death. The abnormal expression of protein tyrosine kinase can lead to the disorder of cell proliferation regulation, and then lead to the occurrence of tumor. In addition, abnormal expression of protein tyrosine kinases is also closely related...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4985A61P35/00A61P35/04A61P35/02
CPCC07D487/04C07D519/00A61K31/4985A61K31/4995A61P35/00A61P35/02A61P35/04
Inventor 王勇赵立文谢同沙向阳苏小川张波叶嘉伟
Owner NANJING SANHOME PHARM RES & DEV CO LTD
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