CN112279843B

CN112279843B - Nitrogen-containing heterocyclic compound with antidepressant activity

Info

Publication number: CN112279843B
Application number: CN202011330304.6A
Authority: CN
Inventors: 任力杰; 谭回; 胡诗雨; 冯宏业; 王洋; 雷志浩
Original assignee: Shenzhen Second Peoples Hospital
Current assignee: Shenzhen Second Peoples Hospital
Priority date: 2020-11-24
Filing date: 2020-11-24
Publication date: 2023-05-16
Anticipated expiration: 2040-11-24
Also published as: CN112279843A

Abstract

The invention relates to a compound with antidepressant activity, a preparation method and application thereof, and relates to the technical field of medicines.

Description

Nitrogen-containing heterocyclic compound with antidepressant activity

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a compound with antidepressant activity, and also relates to a preparation method, a pharmaceutical composition and application of the compound.

Background

Depression is a common mental disorder, which is an affective disorder. Along with the continuous acceleration of life rhythm, the mental pressure of people is gradually increased, depression is a common disease and a high incidence of modern society, the incidence rate of the depression is rapidly rising, and according to incomplete statistics, the current worldwide depression patients account for 3-5% of world population, and the depression patients are almost seen in all age stages, and if the depression patients are not recognized and treated in time, serious consequences (such as suicide, disability, excessive medical resource waste and the like) can be brought. According to the < 2002 world health report > published by the world health organization, depression has now become the fourth world disorder, by 2022, and depression is likely to become the 2 nd disease next to heart disease.

The main treatment methods of depression include antidepressant therapy, psychological therapy, electric tic therapy, transcranial microcurrent stimulation therapy, reflex therapy, self-treatment therapy, etc.

Duloxetine is a third generation antidepressant drug, 5-hydroxytryptamine, and norepinephrine reuptake inhibitor, developed by Gift America. Increasing the levels of these neurotransmitters by inhibiting 5-hydroxytryptamine and norepinephrine reuptake increases the 5-hydroxytryptamine and norepinephrine concentrations in the brain and spinal cord, which increases the 5-hydroxytryptamine and norepinephrine concentrations in the brain, and acts as an antidepressant.

CN102333762B reports that ethylamine compounds have NMDA (N-methyl-D-aspartate) receptor antagonist activity and can be used for the treatment of depression. Therefore, the inventor introduces duloxetine and ethylamine compounds into the same molecular structure through the principles of molecular splicing and bioelectronic isostere, and screens out a novel compound with potential depression treatment activity through a forced swimming test of mice.

In summary, although various chemical drugs and natural drugs are in different research stages, there is no drug which splices duloxetine and ethylamine compounds fragments in antidepressant drugs on the market at present. Therefore, the development and research of novel compounds having therapeutic activity for depression is of great clinical significance.

Disclosure of Invention

The technical problems to be solved by the invention are as follows:

in a first aspect of the present invention, there is provided a compound of formula I and pharmaceutically acceptable salts thereof, having the structure:

preferably, the pharmaceutically acceptable salt is selected from: hydrochloride, hydrobromide, phosphate, sulfate, acetate, oxalate, tartrate, and the like;

in another aspect of the present invention, there is provided a process for the preparation of a compound of formula I, which is depicted in the scheme below:

duloxetine reacts with chloroacetyl chloride to generate a compound 2, and the compound 2 reacts with a compound 3 in a substitution way to generate a compound shown in a formula I.

The specific reaction steps are as follows: adding duloxetine, triethylamine and methylene dichloride into a reaction bottle, stirring uniformly at room temperature, dropwise adding chloroacetyl chloride, stirring at room temperature for reaction for 1-5h, adding water after the reaction is finished, extracting with methylene dichloride, standing for separating liquid, combining organic phases, drying with anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain a tan viscous liquid compound 2.

Adding the prepared compound 2 and acetonitrile into a reaction bottle, stirring until the compound 2 and the acetonitrile are fully dissolved, adding triethylamine and catalytic amount of anhydrous sodium iodide, stirring at room temperature, adding an amine compound 3, carrying out reflux reaction for 4-8h, and carrying out aftertreatment to obtain a target product I.

Preferably, the molar ratio of compound 2 to compound 3 is 1:1-2, preferably 1:1.

In another aspect, the invention provides a pharmaceutical composition, which comprises a compound shown in a formula I or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers and excipients.

In another aspect, the invention relates to the use of a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of an antidepressant; preferably, the depression is a major depressive disorder.

Compared with the prior art, the invention has the beneficial effects that:

(1) The invention provides a new antidepressant compound with nitrogen-containing heterocycle, which widens the range of the existing antidepressant therapeutic compound and can be used as a lead compound to continue optimization;

(2) The compound shown in the formula I shows good pharmacological activity in a forced swimming test of mice, and can be used for preventing and treating depression.

Detailed Description

The present invention is described in more detail below to facilitate an understanding of the present invention. The compounds of the present invention may be prepared by a number of methods well known to those skilled in the art of synthesis. The compounds of formula I may be prepared using the reactions and techniques listed below, along with methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent suitable for the reagents and materials used and for the transformation to be effected. Furthermore, in the synthetic methods described below, it should be understood that all suggested reaction conditions (including choice of solvents, reaction atmospheres, reaction temperatures, experimental durations, and post-treatment procedures) are chosen as standard conditions for the reaction, which should be readily ascertained by one skilled in the art of organic synthesis. Not all compounds falling within a given class may be compatible with certain reaction conditions required in certain of the methods. These limitations on substituents compatible with the reaction conditions will be apparent to those skilled in the art and alternative methods may be used.

Example 1: synthesis of Compound I

Duloxetine (0.034 mol) was dissolved in a 250mL reaction flask containing 100mL of dichloromethane, triethylamine (0.068 mol) was added thereto, stirred at room temperature uniformly, chloroacetyl chloride (0.05 mol) was added dropwise thereto, stirred at room temperature for 2.5 hours, 100mL of water was added thereto after the reaction was completed, extracted with dichloromethane (50 mL x 2), left to stand for separation, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound 2 as a tan viscous liquid.

Adding the compound 2 prepared in the previous step and 100mL of acetonitrile into a 250mL reaction bottle, stirring until the compound 2 and 100mL of acetonitrile are fully dissolved, adding triethylamine (0.06 mol) and a catalytic amount of anhydrous sodium iodide (0.01 g), stirring at room temperature, adding amine compound 3 (0.04 mol), carrying out reflux reaction for 7h, carrying out reduced pressure evaporation to remove a solvent after the reaction is finished, adding 60mL of water, extracting dichloromethane (60 mL of 2), standing for separating liquid, combining organic phases, drying the anhydrous sodium sulfate, carrying out reduced pressure evaporation to remove the solvent, and obtaining a light yellow gelatinous target product I, wherein the HPLC purity is 99.1%. The total yield of the two steps of reaction is 51.6 percent based on duloxetine.

The molecular formula: c (C) ₃₅ H ₃₇ N ₃ O ₂ S；ESI-MS：564.57[M+H] ⁺

¹ H NMR(400MHz，CDCl ³ )δ1.43(s，6H)，2.17(s，1H)，2.38(d，2H)，3.19(m，2H)，3.46(d，2H)，3.63(d，3H)，4.29(m，1H)，4.99(d，1H)，6.61(m，1H)，6.83-7.40(m，3H)，7.64-8.61(m，Ar-H，15H)。

Example 2: anti-depression activity study in animals of the compound shown in formula I

Preliminary studies of in vivo antidepressant action were performed on preferred compounds using the mice forced swimming "immobility" experiment in "acquired despair experiments (forced swimming test) with duloxetine as a positive control.

1. Experimental method

The drug dose of the compound to be tested is firstly set to be 10mg/kg and 30mg/kg, if the drug dose produces obvious effect (reducing the immobility time of the mice), the dose is properly regulated down, if no effect (not reducing the immobility time of the mice) is produced, the dose is regulated up, or the drug dose to be tested is inserted into the above 2 doses according to the proportion between the tested doses, and the drug dose to be tested is determined according to specific conditions. Duloxetine hydrochloride and each test compound were dissolved in 50% PEG400 and then sonicated for 30min.

Mice with acceptable body weight were screened and randomly grouped, 10 per group, with vehicle control, positive control and drug-dosed groups established several days prior to the experiment. The administration group was administered by lavage (ig) for 1h before each experiment. After the administration, the mice were placed in a transparent forced swimming cylinder (25 cm in height, 10cm in diameter) for 6min, 15cm in depth, and at a water temperature of 23-25 ℃. The camera records the video for manual analysis and records the immobility time within 4min after the mice, and the video analyst does not know the administration condition of the animals.

2. Experimental results

Table 1: experimental results of "motionless" in forced swimming of mice

Compounds of formula (I)	Dosage (mg/Kg)	Time of immobility(s)
			CMC-Na	30	116±39
Duloxetine hydrochloride	30	35±13 ^#
			Group I Compounds	30	18±6 ^#
Group I Compounds	10	25±10 ^#

Note that: in comparison with the control group, ^# P＜0.05

the test results show that: in the experiment of forced swimming of mice, the compound of the formula I can obviously shorten the time of stopping immobility due to despair, and the drug effect generated at the doses of 10mg/kg and 30mg/kg is obviously better than that of the positive drug duloxetine at 30mg/kg, and has extremely obvious difference compared with a solvent control group, so that the compound of the formula I has stronger in-vivo antidepressant activity.

Example 3: other biological evaluation of Compounds of formula I

NMDA receptor antagonist activity can be measured in vitro as follows: the ability of compounds to inhibit the binding of the receptor antagonist 10, 11-dihydro-5-methyl-5H-dibenzo [ a, d ] cycloheptene-5, 10-imine (MK 801) to the receptor is measured as described in Foster and Wong, br.J. Pharmacol, 91,403-409 (1987).

The test results show that: compounds of formula I MK801 binding IC ₅₀ The value was 0.5. Mu.M.

The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations to the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims

1. A compound of formula I and pharmaceutically acceptable salts thereof, having the structure:

2. a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof selected from: hydrochloride, hydrobromide, phosphate, sulfate, acetate, oxalate, tartrate.

3. A process for the preparation of a compound of formula I as defined in claim 1, which is carried out by the following reaction scheme:

4. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. Use of a compound of formula I as defined in any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof for the manufacture of an antidepressant.