1, 5-benzodiazepine compound containing thiazolyl and ester and application of compound

A technology for benzodiazepines and compounds, which is applied in the field of medicinal chemistry, can solve the problems of no drug prospect and low bacteriostatic activity, and achieves the effects of improving pharmacokinetic properties, strong antibacterial efficacy and high yield

Active Publication Date: 2014-08-06
HEBEI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In 2011, Indian chemist Dawane also reported that 1,5-benzodiazepines substituted by the 2-position azole ring have good antibacterial effects, but the 1,5-benzodiazepines found so far The antibacterial activity of azapine derivatives against fungi and bacteria is not high, and only when the dosage is large, they show antibacterial activity, so they do not have a good prospect for drug production

Method used

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  • 1, 5-benzodiazepine compound containing thiazolyl and ester and application of compound
  • 1, 5-benzodiazepine compound containing thiazolyl and ester and application of compound
  • 1, 5-benzodiazepine compound containing thiazolyl and ester and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 2-(2-thiazole)-3-carboethoxy-4-methyl-1,5-benzodiazepine

[0028] In a 50 mL one-necked flask, add 2 mmol of N-o-anilino-β-enaminoethyl ester and 20 mL of anhydrous methanol, then add 2 mmol of 2-thiazole aldehyde, and react at 0°C for 8 hours. Stop the reaction, let it stand, and get a solid by suction filtration, and recrystallize with absolute ethanol to get a light yellow solid, m.p: 166~168 ℃, yield 83.8%, MS [M+H + ]: 316; 1 H NMR (CDCl 3 , 500MHz) δ(ppm): 6.58-7.64 (5H, m, -C 6 h 3 , -C 3 h 2 NS), 6.11 (1H, s, -NH), 6.15 (1H, s, -CH), 4.86 (1H, s, -NH), 4.11-4.15 (2H, -COOCH 2 ), 2.60 (3H, s, -CH 3 ), 1.17-1.19 (3H, t, -CH 2 CH 3 ). IR (KBr cm-1) ν 3321 (N-H), 1680 (C=O), 1632 (C=C). The solid was determined to be 2-(2-thiazole)-3-carboethoxy-4-methyl-1,5-benzodiazepine.

Embodiment 2

[0029] Example 2 Preparation of 2-(2-thiazole)-3-carboethoxy-4-methyl-8-bromo-1,5-benzodiazepine

[0030] The same method as in Example 1 is carried out, except that N-(4-bromo-2-phenylamino)-β-enaminoethyl ester is used instead of N-o-anilino-β-enaminoethyl ester, and it needs to be reacted Concentrated under reduced pressure after completion, the residue was separated by column chromatography and rotary evaporated to obtain a light yellow granular solid, m.p: 168~170 °C, yield 87.8%, MS [M+H + ]: 394; 1 H NMR (CDCl 3 , 500MHz) δ(ppm): 6.48-7.67 (5H, m, -C 6 h 3 , -C 4 h 2 NS), 6.12 (1H, s, -CH), 6.11 (1H, s, -NH), 4.91 (1H, s, -NH), 4.11-4.15 (2H, q, -COOCH 2 ), 2.57 (3H, s, -CH 3 ), 1.17-1.20 (3H, t, -CH 2 CH 3 ). IR (KBr, cm-1) ν 3340 (N-H), 1670 (C=O), 1625 (C=C). The solid was determined to be 2-(2-thiazole)-3-carboethoxy-4-methyl-8-bromo-1,5-benzodiazepine.

Embodiment 3

[0031] Example 3 Preparation of 2-(2-thiazole)-3-carboethoxy-4,8-dimethyl-1,5-benzodiazepine

[0032] The same method as in Example 1 is carried out, except that N-(4-methyl-2-phenylamino)-β-enaminoethyl is used instead of N-o-anilino-β-enaminoethyl, and the product is light Yellow granular solid, m.p: 162~164 ℃, yield 90.1%. MS[M+H + ]: 330; 1 H NMR (CDCl 3 , 500MHz) δ(ppm): 6.40-7.65 (5H, m, -C 6 h 3 , -C 3 h 2 NS), 6.16 (1H, s, -NH), 6.12 (1H, s, -CH), 4.81 (1H, s, -NH), 4.10-4.14 (2H, q, -COOCH 2 ), 2.57 (3H, s, -CH 3 ), 2.12 (3H, s, -CH 3 ), 1.16-1.18 (3H, t, -CH 2 CH 3 ). IR (KBr, cm-1) ν 3317 (N-H), 1674 (C=O), 1621 (C=C). The solid was determined to be 2-(2-thiazole)-3-carboethoxy-4-methyl-8-methyl-1,5-benzodiazepine

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Abstract

The invention discloses a 1, 5-benzodiazepine compound containing thiazolyl and ester and an application of the compound, and a structural formula of the compound is represented by a formula (I). The compound has a broader spectrum and higher activity for inhibiting funguses ad bacteria, and in-vitro antibacterial activity test result shows that the compound has a more obvious activity inhabiting effect and a higher killing effect on two types of funguses including cryptococcus neoformans clinical strains and standard strains as well as candida albicans, has a very high activity inhabiting effect and a very high killing effect on two types of bacteria including positive bacteria, namely staphylococcus aureus, as well as negative bacteria, namely escherichia coli, and can be taken as a candidate molecule and a lead compound for an antibacterial agent; and the structural formula of the compound is represented as the instruction shown.

Description

technical field [0001] The invention relates to a medicinal compound, in particular to a 1,5-benzodiazepine compound containing an ester group and a thiazole functional group, and belongs to the technical field of medicinal chemistry. Background technique [0002] 1,5-Benzodiazepine (1,5-benzodiazepine) is a class of heterocyclic compounds with important pharmacological and physiological activities, and is a class of valuable active compounds in the development of new drugs. In the study of benzodiazepine compounds, it was found that antibacterial activity is also a common feature of this type of compound. In 2008, Song Huacan's research group reported 1,5-benzodiazepines substituted by 2,4 aryl groups. The antibacterial activity of Zhuo compound on some strains of Helicobacter pylori is equivalent to that of metronidazole, and it also has certain inhibitory effects on Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. In 2011, Indian chemist Dawane also r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04A61K31/5513A61P31/04A61P31/10
CPCC07D417/04Y02A50/30
Inventor 王兰芝李晓庆
Owner HEBEI NORMAL UNIV
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