阅读说明：本技术 化合物as1842856的用途 (Application of compound AS1842856 ) 是由 朱维莉 陆林 时杰 丁增波 李素霞 武潇 黄英杰 吴萍 薛言学 于 2019-11-26 设计创作，主要内容包括：本发明公开了化合物AS1842856的用途。本发明化合物AS1842856或其药用盐应用于制备预防和/或治疗合成毒品成瘾的药物中。本发明化合物AS1842856实验证明在小鼠甲基苯丙胺戒断模型中表现出明显的抗焦虑作用、抗抑郁作用和改善认知功能的作用,说明其具有预防和/或治疗合成毒品成瘾的作用,能够用于治疗甲基苯丙胺的戒断症状,从而减少复吸。(The invention discloses application of a compound AS 1842856. The compound AS1842856 or the medicinal salt thereof is applied to preparing the medicine for preventing and/or treating the addiction to the synthetic drugs. Experiments of the compound AS1842856 prove that the compound AS1842856 has obvious anxiolytic effect, antidepressant effect and cognitive function improving effect in a mouse methamphetamine withdrawal model, so that the compound AS1842856 has the effect of preventing and/or treating addiction to synthetic drugs, can be used for treating withdrawal symptoms of methamphetamine, and further reduces relapse.)

1. The application of the compound AS1842856 or the medicinal salt thereof in preparing the medicament for preventing and/or treating addiction to synthetic drugs.

2. Use according to claim 1, characterized in that: the synthetic drug addiction comprises methamphetamine addiction.

A medicament for the prevention and/or treatment of addiction to synthetic drugs of abuse, the active ingredient of which is said compound AS1842856 or a pharmaceutically acceptable salt thereof.

4. The medicament according to claim 3, wherein: the dosage form of the medicine is a pharmaceutically acceptable dosage form.

5. The drug according to claim 3 or 4, wherein the drug is in the form of at least selected from the group consisting of an oral dosage form, an injectable dosage form, an inhaled dosage form and a sublingual dosage form.

6. The drug substance of according to any one of claims 3 to 5, wherein the unit dose of administration of the drug substance is 15-50 mg/kg.

Technical Field

The invention relates to application of a compound AS1842856, in particular to application of the compound AS1842856 in preparing a medicament for preventing and/or treating addiction to synthetic drugs.

Background

At present, the problem of drug abuse in the world is still completely solved, and according to data of United nations drug and crime problem office (UNODC) < 2017 world drug report >, 2.5 million people are using illegal drugs in the world by 2015. The number of diseases due to drug abuse is rising year by year, thereby causing huge economic loss and serious social problems. In recent years, the abuse problem of drugs is changed newly, the proportion of people abusing traditional drugs of opium such as heroin is reduced, and the proportion of people abusing novel synthetic drugs is increased remarkably. The ministry of public security, "2018 report of the situation of Chinese drugs", indicates that methamphetamine (commonly known as "methamphetamine") has become the "first drug" of abuse by the end of 2018. 240.4 million drug addicts exist in China, wherein the number of the drug addicts abusing the methamphetamine is up to 135 million, which accounts for 56.1 percent of the total number of the drug addicts, and the methamphetamine has replaced heroin and becomes the drug with the most abused number in China. According to the characteristics of methamphetamine and other synthetic drugs, the method has the directive principle of targeted diagnosis and treatment. The harmful use of the synthetic drugs should be discovered and intervened in early stage, and the comprehensive treatment mode of medicine, psychology and society is mainly adopted to promote the comprehensive rehabilitation of the body, psychology and society and reestablish the healthy life style, thereby preventing relapse.

For example, a plurality of epidemiological evidences indicate that long-term smoking can significantly increase the risk of type 2 diabetes mellitus, forkhead transcription factor O subfamily 1(forkhead box transcription factor O1, FoxO1) is subgroups of forkhead protein family, and plays an important role in the exertion of the insulin action of fat cells and islet β cells, and animal experimental studies show that inhibiting FoxO1 in the brain of an obese rat can reverse obesity caused by high-fat diet.

The compound AS1842856 is synthetic FoxO1 selective small molecule inhibitors with CAS number 836620-48-5, named 5-amino-7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or 5-amino-7- (cyclohexylamino) -1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, and its structural formula is shown in formula I below:

the study found that compound AS1842856 was able to dose-dependently bind to dephosphorylated FoxO1, translocate FoxO1 from the nucleus to the cytoplasm, leading to increased p-FoxO1 protein levels in the cytoplasm and decreased FoxO1 protein levels in the nucleus, inhibiting FoxO1 activity. However, no preclinical study evidence has been reported for the FoxO1 inhibitor AS1842856 in the field of treating addiction to synthetic drugs.

Disclosure of Invention

The invention aims to provide application of a compound AS1842856, in particular to application of the compound AS1842856 or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating addiction to synthetic drugs.

The invention provides an application of a compound AS1842856 or a medicinal salt thereof in preparing a medicament for preventing and/or treating addiction to synthetic drugs.

In the above application, the addiction to the synthetic drug includes addiction to methamphetamine, and the synthetic drug may specifically be dextromethorphan hydrochloride.

The invention provides medicaments for preventing and/or treating addiction to synthetic drugs, wherein the active ingredient of the medicaments is the compound AS1842856 or pharmaceutically acceptable salts thereof.

In the above drugs, the dosage form of the drug is a pharmaceutically acceptable dosage form.

In the above medicine, the dosage form of the medicine is at least of oral dosage form, injection dosage form, inhalation dosage form and sublingual dosage form.

In the above drugs, the unit dosage of the drug can be 15-50 mg/kg, specifically 30mg/kg, 15-30 mg/kg, 30-50 mg/kg or 20-40 mg/kg.

In the invention, the auxiliary material of the medicine is a conventional auxiliary material known in the field, and can be carboxymethyl cellulose-sodium.

In the invention, when a liquid preparation is adopted, the concentration of the medicine can be 0.5-5 mg/ml, specifically 1.5mg/ml, 0.5-5 mg/ml or 1-3 mg/ml, specifically preparation methods comprise dissolving 15mg AS1842856 in 10ml of 1% carboxymethyl cellulose-sodium (CMC-Na) to obtain a uniform suspension (if the medicine powder has agglomerates, the powder can be scattered by vortex and ultrasonic wave), and specifically oral administration is adopted.

The invention has the following advantages:

experiments of the compound AS1842856 prove that the compound AS1842856 has obvious anxiolytic effect, antidepressant effect and cognitive function improving effect in a mouse methamphetamine withdrawal model, so that the compound AS1842856 has the effect of preventing and/or treating addiction to synthetic drugs, can be used for treating withdrawal symptoms of methamphetamine, and further reduces relapse.

Drawings

FIG. 1 is a flowchart of the preparation of a mouse methamphetamine withdrawal model.

Figure 2 is a graphical representation of the effect of compound AS1842856 on anxiety behavior in a new environment inhibition feeding experiment in methamphetamine-weaned mice.

Figure 3 is a graphical representation of the effect of compound AS1842856 on anxiety behavior in elevated plus maze experiments in methamphetamine-weaned mice.

Figure 4 is a graphical representation of the effect of compound AS1842856 on the depressive behaviour of methamphetamine-withdrawal mice in social interaction experiments.

Figure 5 is a schematic representation of the effect of compound AS1842856 on depressive behavior in forced swim experiments in methamphetamine-weaned mice.

Figure 6 is a graphical representation of the effect of compound AS1842856 on depressive behavior in tail suspension experiments in methamphetamine-withdrawal mice.

Figure 7 is a graphical representation of the effect of compound AS1842856 on cognitive function in methamphetamine-withdrawal mice in a novel object recognition experiment.

Detailed Description

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

In the following examples, the experimental animals were 4-6 week C57BL/6 male mice (weight 20-22g) purchased from experimental animals technologies ltd, viton, beijing, license number: SCXK (Kyoto) 2016-.

In the following examples, the methamphetamine is dextro-methamphetamine hydrochloride, which is provided by the ministry of public Security for drug inhibition information technology center (lot number 2043-. The intraperitoneal injection dose of the mouse methamphetamine is 5mg/kg (ip), 2.5mg of dextro-methamphetamine hydrochloride is dissolved in 10ml of sterile normal saline, and the intraperitoneal injection volume of the mouse is 0.2ml/10g of body weight.

In the examples below, compound AS1842856 is available from MCE corporation, USA.

In the following examples, compound AS1842856 was prepared according to a method comprising the steps of intragastric administration of 30mg/kg in AS1842856 mice, intragastric administration of 0.2ml/10g body weight in a volume of mice, and formulation of 1.5mg/ml, and specifically prepared by dissolving 15mg AS1842856 in 10ml of 1% sodium carboxymethylcellulose (CMC-Na) to give a homogeneous suspension (which can be vortexed and sonicated if the powder is agglomerated).

The animal behavioral testing methods referred to in the following examples are all routine laboratory procedures, and the specific procedures are as follows:

a new environmental feeding inhibition experiment for mice was conducted in an organic glass box of 42cm x 25cm open at the top, mice were fed daily in the central area, the mice were fasted for 24 hours and then placed alone in the experimental apparatus, and the feeding latency was used as an index for evaluating anxiety-like behavior, i.e., the time (seconds) from the time when the mice were placed in the experimental apparatus until the mouths of the mice were exposed to food, the feeding experiment time was 5 minutes, and the maximum latency was 300 seconds.

Mouse elevated plus maze experiment: the elevated plus labyrinth device consists of two closed arms, two open arms and a central area, wherein the open arms and the closed arms are 33cm long and 5cm wide, the closed arms are 25cm high, the central area is 5cm multiplied by 5cm, and the elevated plus labyrinth is 55cm away from the ground. At the beginning of the test, the mouse was placed in the central area of the apparatus with the mouse head facing the open arm, the mouse was freely moved in the elevated plus maze for 5min, the residence time (seconds) of the mouse in the open arm and the closed arm was recorded, and the experimental results are expressed as the residence time of the mouse in the open arm/the residence time of the mouse in the closed arm.

Mouse social interaction behavior experiment the experiment was performed in an open field of 42cm × 42cm × 25cm the social interaction behavior experiment was divided into two phases, each phase was 2.5 minutes, the interval between the two phases was 30 seconds, th phase C57BL/6 test mice were randomly placed in the corner distal to the interaction area, plastic transparent cartridges of 3cm × 6cm × 25cm covered with small holes were placed in the interaction area, C57BL/6 mice were not placed in the cartridges, C57BL/6 test mice were allowed to move freely in the open field 387387, the time (seconds) that the C57/6 test mice stayed in the interaction area was recorded, C57BL/6 mice were placed in the transparent cartridges, C57BL/6 test mice were again placed in the corner of the open field, the interaction of the C57BL/6 test mice with the transparent cartridges was observed, and the rate of the retention of the C57/6 test mice in the interaction area was recorded BL/6 second phase.

Forced swimming experiment of mice: the forced swimming test is carried out in an organic glass jar with the diameter of 20cm and the height of 30cm, the water depth is 15cm, and the water temperature is 23 +/-1 ℃. When the mouse swims, the mouse is ensured not to be supported by four limbs or the tail, and the nose tip is ensured to be exposed out of the water surface for breathing. 1 day before the experiment, each group of mice was placed in a glass jar for swimming pre-adaptation for 15 minutes. On day 2, a forced swim test was performed. The time for swimming of the mice was 6 minutes, and 2 minutes after the start of the experiment, the time (seconds) for floating and standing of the mice 4 minutes after the start was recorded and used as an index of despair behavior.

Mouse tail suspension experiment: the mouse tail suspension test device is white organic resin with the length of 15cm, the width of 15cm and the height of 50 cm. In the experiment, the mouse is fixed on a suspension rod in an inverted mode at the position of 1cm from the tail tip of the mouse by using a white adhesive tape, the height of the suspension rod to the ground is 50cm, and the standing time (seconds) of the mouse within 6 minutes is recorded, namely when the mouse is passively suspended, no other limb or body movement is caused except limb or body movement caused by breathing.

Mouse new object identification experiment, the experiment was carried out in a 42cm x 25cm plexiglas box, day 1, the mice were individually placed in turn in the plexiglas box for 10 minutes to acclimate, day 2, two identical cylinders a (diameter 5cm, height 4.5cm) were placed in the plexiglas box at the center, the mice were then placed in the plexiglas box for 5 minutes to allow free exploration of the two cylinders (object a), day 3, of which were replaced with new objects (cubes with sides of 4.5cm) (object B), which are different in shape but similar in volume, the mice were then placed in the plexiglas box for 5 minutes again, and the mice's exploration time between object a and object B was recorded (the nose of the mice was less than 2cm from the object).

And (3) data statistics: data analysis used GraphPad Prism7 Software (GraphPad Software Inc.). Results are expressed as mean ± standard error (mean ± SEM), and all data were tested for normal distribution and homogeneity of variance using D' Agostino & Pearson normativity and Brown-Forsythe, respectively. If the data accord with normal distribution and homogeneity of variance, Unpreared t-test is adopted for two groups of data of single factor, and One-way ANOVA analysis is adopted for multiple groups of data of single factor. If the data do not conform to normal distribution and homogeneity of variance, Mann-Whitney test, Kruskal-Wallis One-way ANOVA analysis was used. Pairwise comparisons between groups were analyzed by Tukey's multiple complexes test. P < 0.05 was used as a significant difference criterion.