阅读说明：本技术 一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物及其合成和应用 (Pyridyl imidazobenzodiazepine propionate compound and synthesis and application thereof ) 是由 漆又毛 于 2018-12-28 设计创作，主要内容包括：本发明公开了一种吡啶基咪唑并苯并二氮杂卓丙酸酯(化合物1)及其合成和应用。本发明还提供制备中间体。本发明提供的化合物1具有明显的静脉麻醉活性,静脉麻醉活性等同于阳性对照药瑞马唑仑对甲苯磺酸盐或者瑞马唑仑苯磺酸盐。此外化合物1在小鼠模型实验中可以明显降低,甚至克服了瑞马唑仑苯磺酸盐或者瑞马唑仑对甲苯磺酸盐作为在研药物在临床前动物实验中常见的四肢抖动,昂头,角弓反张等副作用,因此可在制备静脉麻醉药物中的应用。化合物1的结构通式如下,其中各基团和取代基的定义如说明书中所述。<Image he="552" wi="563" file="DDA0002627645510000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses pyridyl imidazobenzodiazepine propionate (compound 1) and synthesis and application thereof. The invention also provides a preparation intermediate. The compound 1 provided by the invention has obvious intravenous anesthetic activity, and the intravenous anesthetic activity is equal to that of a positive control medicament of remazolam p-toluenesulfonate or remazolam benzenesulfonate. In addition, the compound 1 can be obviously reduced in a mouse model experiment, and even overcomes the side effects of extremity shaking, head raising, angle reversal, and the like which are commonly seen in animal experiments before clinical use of remazolen benzene sulfonate or remazolen p-toluenesulfonate as a research medicament, so that the compound can be applied to the preparation of intravenous anesthesia medicaments. The compound 1 has the following structural general formula, wherein the definitions of each group and substituent are described in the specification.)

A pyridylimidazobenzodiazepine propionate compound 1, wherein said compound 1 has the general structural formula:

wherein:

r is selected from the group consisting of: various alkyl groups with short carbon chains, trifluoromethyl, methoxy, nitro, fluorine, chlorine and bromine;

R₁selected from the group consisting of: various alkyl groups with short carbon chains, trifluoromethyl, methoxy, nitro, fluorine, chlorine and bromine;

R₂a pyridine ring with nitrogen in the 2, 3 or 4 position;

R₃various alkyl groups that are short carbon chains;

HX represents any acceptable pharmaceutically acceptable inorganic and organic acids.

Compound 1 according to claim 1, characterized in that the various alkyl groups of the short carbon chain are C1-C6 alkyl groups.

Compound 1 according to claim 1, wherein R and R₁Different.

The compound 1 of claim 1, wherein R is F; r₁Is C1-C6 alkyl; r₂A pyridine ring with nitrogen in the 2-position;

R₃is C1-C6 alkyl.

The compound 1 of claim 1, wherein R is C1-C6 alkyl; r₁Is F; r₂A pyridine ring with nitrogen in the 3-position;

R₃is C1-C6 alkyl.

Compound 1 according to claim 1, wherein compound 1 is selected from the group consisting of:

a pyridylimidazobenzodiazepine propionate compound 10 having the following general structural formula:

wherein R is selected from the group consisting of: various alkyl groups with short carbon chains, trifluoromethyl, methoxy, nitro, fluorine, chlorine and bromine;

R₁selected from the group consisting of: various alkyl groups with short carbon chains, trifluoromethyl, methoxy, nitro, fluorine, chlorine and bromine;

R₂a pyridine ring with nitrogen in the 2, 3 or 4 position;

R₃various alkyl groups with short carbon chains.

A process for the preparation of a pyridylimidazobenzodiazepine propionate compound 1 according to claim 1, which is obtained by the following synthetic steps:

adopting anthranilic acid pyridine 2 with various substituents on 3, 4 positions and Boc-L-glutamic acid-5 ester 3 as starting raw materials to generate 2- (Boc-L-glutamic acid-5 ester acyl) amino-3, 4-disubstituted benzoyl pyridine 4 in the presence of DCC; removing Boc protecting group under the action of acid 5 to obtain 2- (L-glutamic acid-5-ester acyl) amino-3, 4-disubstituted benzoyl pyridine salt 6, and performing intramolecular condensation in the presence of sodium bicarbonate to obtain 3, 4-disubstituted benzodiazepine propionate 7; then reacting with (R) -1-amino-2-propanol 8 to generate (R) -N- (3, 4-disubstituted benzodiazepine propionate) amino-2-propanol 9, carrying out oxidative ring-closure reaction with DMP to obtain pyridyl imidazobenzodiazepine propionate 10, and carrying out salt-forming reaction with acid 5 to obtain a target product pyridyl imidazobenzodiazepine propionate compound 1;

the synthetic reaction route is as follows:

r, R therein₁、R₂、R₃HX is as defined in claim 1; DMP stands for Des-Martin oxidant.

A pharmaceutical composition, comprising:

1) an anaesthetically effective amount of one or more of compound 1 of claim 1 and/or compound 10 of claim 7; and

2) a pharmaceutically acceptable carrier.

Use of the pyridylimidazobenzodiazepine propionate compound 1 according to claim 1, in the preparation of intravenous anaesthetics.