2-aminomethylpyridylnicotinamides and preparation method and application thereof

A compound, nicotinamide technology, applied in the field of medicinal chemistry, can solve the problem of no MDR reversal agent on the market

Inactive Publication Date: 2017-04-19
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although research on third-generation P-gp inhibitors has brought hope for the reversal of tumor multidrug resistance, there is still no MDR reversal agent on the market

Method used

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  • 2-aminomethylpyridylnicotinamides and preparation method and application thereof
  • 2-aminomethylpyridylnicotinamides and preparation method and application thereof
  • 2-aminomethylpyridylnicotinamides and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Preparation of 2-((pyridine-4-methylene)amino)nicotinic acid (3)

[0085]

[0086] Add 2-chloronicotinic acid (25.3mmol), copper oxide (catalytic amount), and potassium carbonate (25.3mmol) into a 100ml round bottom flask, stir at room temperature for 20min, add 4-methylaminopyridine (50.6mmol), and heat at 110°C 2h. Then add ethyl acetate and stir to room temperature, filter with suction, wash the filter cake twice with ethyl acetate, dissolve in water (20ml), adjust to pH 5-6 with 4N hydrochloric acid, let stand to precipitate, filter with suction, dry the filter cake, The obtained crude product was further purified by hot beating with ethanol, and filtered with suction to obtain 5.16 g of off-white solid with a yield of 89% and a melting point of 197-199°C.

[0087] 1 H NMR (300MHz, DMSO-d 6 ) δppm: 8.61 (d, J=5.8Hz, 1.0H, ArH), 8.48 (s, 2H, ArH), 8.19 (dd, J=4.7, 1.9Hz, 1H, ArH), 8.11 (dd, J=7.7 , 1.9Hz, 1H, ArH), 7.29(d, J=4.7Hz, 2H, ArH), 6.64(dd, J=7.7, 4....

Embodiment 2

[0089]Preparation of N-(3-(methoxy)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-1)

[0090]

[0091] Compound 3 (6mmol), 3-methoxyaniline (5mmol), EDCI (7.2mmol), HOBT (7.2mmol) were dissolved in DMF, stirred at room temperature for 16h, then added 50ml of water to the reaction solution, ethyl acetate ( 30ml×3) extraction, combined organic phases, washed with saturated sodium carbonate solution (20ml×2) and saturated brine (20ml×2), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (dichloromethane / methanol, 50:1, v / v), purified to obtain 0.88 g of white solid, yield 53%, melting point: 113-115°C.

[0092] 1 H NMR (300MHz, DMSO-d 6 )δppm: 10.59 (s, 1H, -CONH-), 9.23 (s, 1H, ArH), 8.87 (d, J=5.4Hz, 2H, ArH), 8.41 (d, J=7.0Hz, 1H, ArH) , 8.07(d, J=5.4Hz, 3H, ArH), 7.45(s, 1H, ArH), 7.32(d, J=6.9Hz, 2H, ArH), 6.97(d, J=5.7Hz, 1H, ArH ), 6....

Embodiment 3

[0094] Preparation of 2-((pyridine-4-methylene)amino)-N-(3,4,5-(trimethoxy)phenyl)nicotinamide methanesulfonate (I-2)

[0095]

[0096] Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) 3,4,5-(trimethoxy)aniline (5mmol) to obtain compound I-2 to obtain 1.21g of white solid with a yield of 61%. Melting point: 216-218°C.

[0097] 1 H NMR (300MHz, DMSO-d 6 )δppm: 10.32 (s, 1H, -CONH-), 8.83 (d, J = 6.1Hz, 3H, ArH), 8.20 (d, J = 7.3Hz, 1H, ArH), 8.10 (d, J = 4.1Hz , 1H, ArH), 7.97 (d, J=5.9Hz, 2H, ArH), 7.20 (s, 2H, ArH), 6.85-6.67 (m, 1H, -NH-), 4.94 (s, 2H, -NHC H 2 -), 3.78(s, 6H, -OCH 3 ), 3.65(s, 3H, -OCH 3 ), 2.37(s, 6H, -CH 3 ); 13 C NMR (75MHz, DMSO-d 6 )δ: 162.22, 155.04, 151.12, 149.22, 144.38, 140.57, 137.08, 133.41, 125.26, 116.37, 108.08, 101.24, 60.70, 56.83, 43.29, 38.57, 36.02]; ESI-MS m / z: 3 + ;Anal.calcd.For C 23 h 28 N 4 o 10 S 2 : C, 47.25; H, 4.83; N, 9.58; S, 10.97; Found: C, 47.27; H, 4.70; N, 9.71; S, 10.82....

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Abstract

The invention relates to a compound as shown in the general formula (I) and salt thereof. The compound has the effect of high reversal of tumor multidrug resistance (MDR). The activity is far higher than that of verapamil, and the cytotoxicity is small. The invention further relates to a preparation method of the compound and a pharmaceutic preparation containing the compound. (Please see the specification for the formula)

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of P-glycoprotein inhibitors, a preparation method thereof and the application of the compounds in multidrug resistance reversal agents. Background technique [0002] Tumor is one of the major diseases that threaten human health and life. Chemotherapy plays an irreplaceable role as the main method to treat tumors. However, due to the emergence of multidrug resistance (MDR) in tumor cells, the efficacy of chemical drugs is greatly reduced. The so-called MDR refers to that after cancer patients receive chemotherapy drugs, tumor cells develop resistance to one chemotherapy drug, and at the same time, they also develop cross-resistance to other chemotherapy drugs that have not been exposed to, or have completely different structures and mechanisms of action. As a result, the clinical curative effect is reduced or ineffective. Studies have shown that 90% of tum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82C07D417/14C07D401/14C07D409/14A61K31/455A61K31/496A61K31/5377A61P35/00A61P35/02
CPCC07D213/82C07D401/14C07D409/14C07D417/14
Inventor 黄文龙钱海潘渺博邱倩倩强浩石炜崔建
Owner CHINA PHARM UNIV
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