CN-121991109-A - ROS triggered hydrogen sulfide donor derivative and preparation method and application thereof

CN121991109ACN 121991109 ACN121991109 ACN 121991109ACN-121991109-A

Abstract

The invention relates to the technical field of medicaments, in particular to a ROS triggered hydrogen sulfide donor derivative, a preparation method and application thereof, and the synthesis method of the beta-carboline hydrogen sulfide donor derivative is simple, and the beta-carboline hydrogen sulfide donor with double functions can be obtained by condensing 4-phenylboronic acid pinacol ester thiobenzyl alcohol with different beta-carboline derivatives substituted by 3-isothiocyanate. The compound can identify excessive oxygen free radicals generated in the myocardial ischemia reperfusion process, simultaneously release hydrogen sulfide with vascular protection effect and beta-carboline derivatives with myocardial protection activity, simultaneously protect damaged cardiac muscle from two aspects, has less influence on normal cells, and provides a new choice for research and development of medicaments for treating ischemic heart diseases.

Inventors

ZHOU MENG
ZHANG RONGHONG
LIN XIANGPING
CHEN TING
LONG JINFENG
YANG LONGFA
Lian Yiying
LIAO SHANGGAO
LI YONGJUN

Assignees

贵州医科大学

Dates

Publication Date: 20260508
Application Date: 20251230

Claims (6)

1. The ROS-triggered beta-carboline hydrogen sulfide donor derivative is characterized in that the structural formula of the ROS-triggered beta-carboline hydrogen sulfide donor compound is shown as the formula (1): Wherein R 1 is proton, alkyl, phenyl or aralkyl, R 2 is proton, alkyl, benzyl or substituted benzyl, R 3 is proton, alkyl, methoxy, hydroxy, nitro, amino or halogen, R 4 is proton or boric acid ester, and the substitution is one or more of halogen, alkyl, haloalkyl or heteroaryl.
2. The ROS-triggered β -carboline hydrogen sulfide donor derivative of claim 1, wherein R 1 is proton, methyl, ethyl, R 2 is proton, methyl, benzyl, o-fluorobenzyl, p-chlorobenzyl, p-trifluoromethylbenzyl, o-methylbenzyl, p-tert-butylbenzyl, difluorobenzyl, 2-pyridinebenzyl, 4-pyridinebenzyl, R 3 is proton, methyl, methoxy, hydroxy, R 4 is proton, borate.
3. The ROS-triggered β -carboline hydrogen sulfide donor derivative of claim 1, wherein the ROS-triggered β -carboline hydrogen sulfide donor compound is 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-methyl-9- (4- (trifluoromethyl) benzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithioate, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (9- (4-fluorobenzyl) -1-methyl-9H-pyrido [3,4-b ] indole) -3-aminodithioate, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (9-benzyl-1-methyl-9H-pyrido [3,4-b ] indole) -3-aminodithio ate, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (9- (3, 5-difluorobenzyl) -1-methyl-9H-pyrido [3,4-b ] indole) -3-aminodithio ate 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (9- (2-fluorobenzyl) -1-methyl-9H-pyrido [3,4-b ] indole) -3-aminodithio acid ester, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-methyl-9- (2- (trifluoromethyl) benzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithio-ate, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (9- (4-chlorobenzyl) -1-methyl-9H-pyrido [3,4-b ] indole) -3-aminodithio-ate 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (9- (4- (tert-butyl) benzyl) -1-methyl-9H-pyrido [3,4-b ] indole) -3-aminodithio acid ester, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-methyl-9- (4-methylbenzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithioate, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-methyl-9- (2-methylbenzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithioate 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-ethyl-9- (2-methylbenzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithio acid ester, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-ethyl-9- (4-fluorobenzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithio-ate, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (9-benzyl-1-ethyl-9H-pyrido [3,4-b ] indole) -3-aminodithio-ate 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-ethyl-9- (4-methylbenzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithio acid ester, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-ethyl-9- (2-pyridine) -9H-pyrido [3,4-b ] indole) -3-aminodithio-ate, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl- (1-ethyl-9- (4-pyridine) -9H-pyrido [3,4-b ] indole) -3-aminodithio-ate 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (9- (4- (tert-butyl) benzyl) -1-ethyl-9H-pyrido [3,4-b ] indole) -3-aminodithio acid ester, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-ethyl-9- (4- (trifluoromethyl) benzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithio-ate, 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-ethyl-9- (2- (trifluoromethyl) benzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithio-ate 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-ethyl-6-methyl-9- (2- (trifluoromethyl) benzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithio acid ester, Any one of 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl- (1-ethyl-6-hydroxy-9- (2- (trifluoromethyl) benzyl) -9H-pyrido [3,4-b ] indole) -3-aminodithio acid ester.
4. A method for preparing a ROS-triggered β -carboline hydrogen sulfide donor derivative according to any one of claims 1-3, comprising the steps of: A. Dissolving the compound 1 in dry THF, adding the compound 2 and NaH, stirring for reaction in an ice bath, adding a saturated NaCl solution, extracting with ethyl acetate, mixing the extracts, spin-drying the organic layer to obtain a crude product, and purifying by normal phase silica gel column chromatography to obtain a product; The structural formula of the compound 1 is as follows: Wherein R 4 is proton or boric acid ester; The compound 2 is 9- (4- (trifluoromethyl) benzyl) -3-methyl-9H-pyridine [3,4-b ] indole, 9- (4-fluorobenzyl) -3-isothiocyanate-1-methyl-9H-pyrido [3,4-b ] indole, 9-benzyl-3-isothiocyanate-1-methyl-9H-pyrido [3,4-b ] indole, 9- (3, 5-difluorobenzyl) -3-isothiocyanate-1-methyl-9H-pyrido [3,4-b ] indole, 9- (2-fluorobenzyl) -3-isothiocyanate-1-methyl-9H-pyrido [3,4-b ] indole, 9- (4-chlorobenzyl) -3-isothiocyanate-1-methyl-9- [2- (trifluoromethyl) benzyl ] -9H-pyrido [3, 4-chlorobenzyl) -3-isothiocyanate-1-methyl-9H-pyrido [3,4-b ] indole, 9- (3, 5-difluorobenzyl) -3-methyl-9H-pyrido [3,4-b ] indole, 9- (2-fluorobenzyl) -3-methyl-9H-pyrido [3,4-b ] indole, 9-methyl-9H-pyrido [3,4-b ] indole 3-isothiocyanato-1-methyl-9- (2-methylbenzyl) -9H-pyrido [3,4-b ] indole, 1-ethyl-3-isothiocyanato-9- (2-methylbenzyl) -9H-pyrido [3,4-b ] indole, 1-ethyl-9- (4-fluorobenzyl) -3-isothiocyanato-9H-pyrido [3,4-b ] indole, 9-benzyl-1-ethyl-3-isothiocyanato-9H-pyrido [3,4-b ] indole, 1-ethyl-3-isothiocyanato-9- (4-methylbenzyl) -9H-pyrido [3,4-b ] indole 1-ethyl-3-isothiocyanato-9- (2-pyridine) -9H-pyrido [3,4-b ] indole, 1-ethyl-3-isothiocyanato-9- (4-pyridine) -9H-pyrido [3,4-b ] indole, 9- (4-tert-butylbenzyl) -1-ethyl-3-isothiocyanato-9H-pyrido [3,4-b ] indole, 1-ethyl-3-isothiocyanato-9- (4-trifluoromethyl benzyl) -9H-pyrido [3,4-b ] indole, 1-ethyl-3-isothiocyanato-9- (2-trifluoromethylbenzyl) -9H-pyrido [3,4-b ] indole, 1-ethyl-3-isothiocyanato-6-methyl-9- (2-trifluoromethylbenzyl) -9H-pyrido [3,4-b ] indole, 1-ethyl-3-isothiocyanato-6-hydroxy-9- (2-trifluoromethylbenzyl) -9H-pyrido [3,4-b ] indole.
5. Use of a ROS-triggered β -carboline hydrogen sulfide donor derivative according to any one of claims 1-3 for the preparation of a medicament for the treatment of myocardial cell oxidative damage.
6. Use of a ROS-triggered β -carboline hydrogen sulfide donor derivative according to any one of claims 1-3 for the preparation of a medicament for ischemic heart disease.

Description

ROS triggered hydrogen sulfide donor derivative and preparation method and application thereof Technical Field The invention relates to the technical field of medicines, in particular to a ROS triggered hydrogen sulfide donor derivative, and a preparation method and application thereof. Background Cardiovascular disease is a major cause of human death worldwide, with prevalence and mortality rates constantly rising, and constitutes a major threat to public health. With the aging of population and the urban process, the number of people suffering from cardiovascular diseases in China is increased year by year, and related death takes the first place of the total death cause of urban and rural residents. Common cardiovascular diseases such as myocardial infarction and coronary heart disease can cause myocardial ischemia, and further cause myocardial tissue necrosis. Clinically, the timely restoration of blood perfusion is a key therapeutic measure for rescuing ischemic myocardium, however, the reperfusion process itself induces further myocardial injury including myocardial apoptosis, infarct size enlargement, arrhythmia and even death, which is a myocardial ischemia/reperfusion injury (Myocardial ischemia-reperfusion injury, MIRI), which has become an important factor affecting the prognosis of myocardial ischemic patients. During reperfusion, mitochondria overproduce Reactive Oxygen Species (ROS) is one of the core pathological mechanisms of MIRI. Excessive ROS not only damages the thiol redox signal path in cells, changes the structure and the function of key proteins through oxidation/nitrification modification, leads to signal transduction disorder, but also can be converted into high-activity nitroxide free Radicals (RNOS), and the high-activity nitroxide free radicals react with biological macromolecules such as DNA, proteins, lipids, saccharides and the like strongly, damage the normal structure and the function of the cells, finally cause vascular dysfunction and aggravate myocardial injury. Therefore, excessive ROS production during reperfusion is a key element in directly inducing cardiomyocyte apoptosis, exacerbating vascular injury and expanding infarct size. Currently, there are significant limitations to drug therapies for MIRI. For example, although hydrogen sulfide (H 2 S) has been demonstrated to have multiple physiological effects such as vasodilation, oxidative stress inhibition, anti-inflammatory and myocardial protection as endogenous gas signal molecules, and studies have shown that its donor can reduce myocardial cell death and infarct size in MIRI models, the existing H 2 S donors still suffer from significant drawbacks such as too fast release, short half-life, poor stability and pungent odor of inorganic donors (e.g., naHS, na 2 S), and the lack of biological activity of chemical fragments remaining after H 2 S release of organic donors, resulting in inefficient structural utilization, often requiring millimole doses for effective H 2 S concentration, and possibly causing toxicity, solubility and non-specific interactions. Meanwhile, the beta-carboline compound is taken as a heterocyclic ring system condensed by pyridine ring and indole pyrrole ring, has proved to have remarkable activity of resisting myocardial ischemia/reperfusion injury (application number: 202010151142.3), but the vascular protection effect of the beta-carboline compound has not been reported yet. Although the combination of β -carbolines with hydrogen sulfide donors for the treatment of myocardial ischemia reperfusion injury has been reported in the patent (application number 202410215114.1), the patent is not strongly recognized as specific for myocardial ischemia reperfusion by thiol-triggered release. Therefore, the design of a novel compound which can specifically respond to excessive ROS in a reperfusion environment and can release H 2 S donor functions and active myocardial protecting pharmacophores through the response has important significance, the compound integrates the triple characteristics of the ROS response release, the H 2 S donor functions and the active myocardial protecting pharmacophores, can efficiently consume the excessive ROS in the reperfusion process, lighten oxidative damage, and simultaneously release two active substances with synergistic protecting effects, namely a beta-carboline derivative with myocardial protecting effect and H 2 S with vascular protecting effect, thereby providing a new path and a new scheme for future treatment of the disease. Disclosure of Invention Aiming at the technical problems, the invention aims to provide the ROS triggered hydrogen sulfide donor derivative, and the preparation method and the application thereof The method is realized by the following technical scheme: A first object of the present invention is to provide a ROS-triggered hydrogen sulfide donor derivative having the structural formula (1): Wherein R 1 is proton, alkyl, phenyl or aralkyl