Imidazol[4,5-b]pyridine thioethanamide derivatives, preparation method and application thereof

A technology of azole thioacetamide and derivatives, which can be used in drug combinations, pharmaceutical formulations, and medical preparations containing active ingredients, etc., can solve the problems of easy mutation of amino acid residues, spread of drug-resistant strains, and clinical application limitations.

Active Publication Date: 2017-12-05
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because the amino acid residues in the binding pocket of NNRTIs are prone to mutations, leading to the generation and spread of drug-resistant strains, the clinical application of such drugs is greatly limited.

Method used

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  • Imidazol[4,5-b]pyridine thioethanamide derivatives, preparation method and application thereof
  • Imidazol[4,5-b]pyridine thioethanamide derivatives, preparation method and application thereof
  • Imidazol[4,5-b]pyridine thioethanamide derivatives, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Methyl 3-bromo-4-(2-(1(4-cyclopropylnaphthalen-1-yl)-1 hydrogen-imidazo[4,5-b]pyridine-2-mercapto)acetamido ) preparation of benzamide (I-1)

[0039] Trifluoromethanesulfonic anhydride (0.35g, 0.142mmol) was slowly added dropwise to a dichloromethane solution of 2-nitro-hydroxypyridine (0.1g, 0.71mmol) and triethylamine (0.11g, 1.065mmol) under stirring in an ice bath Medium (10 mL). After the reaction solution was stirred for three hours, 50 mL of water was added, extracted with dichloromethane (2×10 mL), the organic layer was combined with saturated brine, washed twice, dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 2. Purple-black oil, yield: 94.9%. ESI-MS: m / z 271.3 (M-1), C 6 h 3 f 3 N 2 o 5 S[271.97].

[0040] 4-Bromo-1-naphthylamine (3) (0.50g, 2.25mmol), cyclopropyl boronic acid (0.212g, 2.47mmol), tetrakistriphenylphosphine palladium (0.26g, 0.23mmol), potassium phosphate (1.67g , 7.87mmol) were weighed...

Embodiment 2

[0045] Example 2: Methyl 3-bromo-4-(2-(1-(4-cyclopropylnaphthalen-1-yl)-1 hydrogen-imidazo[4,5-b]pyridine-2-mercapto)acetamide Base) the preparation of benzamide (I-2)

[0046] The operation method is the same as that of Example 1 (I-1), except that methyl 3-bromo-4-(2-chloroacetamido)benzamide is used. White powder, yield: 45.2%.mp: 135-137℃. 1 H NMR (400MHz, DMSO-d 6 ,ppm)δ:10.16(s,1H,NH),8.62(d,1H,J=8.0Hz,pyridylimidazole-H),8.43(d,1H,J=4.0Hz,naphthaline-H),8.13(s, 1H, PhH), 8.08 (d, 1H, J = 8.0Hz, pyridylimidazole-H), 7.95 (d, 1H, J = 8.0Hz, naphthaline-H), 7.72 (d, 2H, J = 8.0Hz, naphthaline- H), 7.53 (t, 1H, J = 8.0Hz, pyridylimidazole-H), 7.49 (d, 1H, J = 8.0Hz, PhH), 7.31 (d, 2H, J = 8.0Hz, naphthaline-H), 7.17 (dd,2H,J 1 =8.0Hz,J 2 =4.0Hz,naphthaline-H),7.12(d,1H,J=8.0Hz,PhH),4.47(m,2H,S-CH 2 ),4.33(q,2H,J=4Hz,CH 2 ), 2.61-2.56(m, 1H, cyclopropyl-H), 1.33(t, 3H, J=4.0Hz, CH 3 ),1.19-1.16(m,2H,cyclopropyl-H),0.91-0.87(m,2H,cyclopropyl-H). 13 C-NMR (100MHz, DM...

Embodiment 3

[0047] Example 3: N-(2-bromo-4 cyanophenyl)-2-(1-(4-cyclopropylnaphthalen-1-yl)-1 hydrogen-imidazo[4,5-b]pyridine-2 -The preparation of mercapto) acetamide (I-3)

[0048] The operation method is the same as that of Example 1 (I-1), except that N-(2-bromo-4cyanophenyl)-2-chloroacetamide is used. White powder, yield: 41.3%.mp: 214-215℃. 1 H NMR (400MHz, DMSO-d 6 ,ppm)δ:10.25(s,1H,NH),8.62(d,1H,J=8.00Hz,pyridylimidazole-H),8.43(d,1H,J=4.0Hz,naphthaline-H),8.25(d, 1H, J = 4.0Hz, PhH), 8.11 (d, 1H, J = 8.0Hz, pyridylimidazole-H), 7.87 (d, 1H, J = 8.0Hz, naphthaline-H), 7.74-7.70 (m, 2H, naphthaline-H), 7.55 (t, 1H, J = 8.0Hz, pyridylimidazole-H), 7.48 (d, 1H, J = 8.0Hz, PhH), 7.31 (dd, 1H, J 1 =8.0Hz,J 2 =4.0Hz,naphthaline-H),7.17(dd,1H,J 1 =8.0Hz,J 2 =4.0Hz,naphthaline-H),7.11(d,1H,J=8.0Hz,PhH),4.49-4.39(m,2H,S-CH 2 ),2.62-2.55(m,1H,cyclopropyl-H),1.19-1.15(m,2H,cyclopropyl-H),0.91-0.87(m,2H,cyclopropyl-H). 13 C-NMR (100MHz, DMSO-d 6 ,ppm)δ:167.41(C=O),156.86,155.62,144....

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Abstract

The invention relates to an imidazole [4,5-b] pyridine mercaptoacetamide derivative represented in a formula I and pharmaceutically acceptable salt, ester or prodrug of the derivative, a preparation method of the derivative and an application of composition containing one or more of the compound to preparation of a drug for treating and preventing HIV (human immunodeficiency virus) infection and anti-leukemia or anti-tumor drugs.

Description

technical field [0001] The invention relates to a derivative and its preparation method and application, in particular to imidazol[4,5-b]pyridine thioacetamide derivatives and its preparation method and application, belonging to the field of medical technology. Background technique [0002] Acquired immunodeficiency syndrome (AIDS, AIDS) is mainly a major infectious disease caused by human immunodeficiency virus type 1 (HIV-1). In the life cycle of HIV, reverse transcriptase (RT) plays a crucial role, responsible for the completion of RNA-guided DNA synthesis, RNA hydrolysis, and DNA-guided DNA synthesis. Therefore, using RT as a target for drug design has the advantages of high inhibitory activity, good selectivity, and low toxicity and side effects, and is an important target for the development of anti-HIV / AIDS drugs. According to different mechanisms of action, HIV reverse transcriptase inhibitors can be mainly divided into nucleoside (t)ide reverse transcriptase inhibi...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07D471/04A61K31/635A61K31/437A61P31/18A61P35/02
CPCC07D471/04
Inventor刘新泳李潇展鹏
OwnerSHANDONG UNIV