CN101817819A - 5-alkoxy-tetrazo[1,5-a]qualone derivative and pharmaceutically acceptable salt thereof serving as antidepressants - Google Patents

Abstract

The present invention relates to new 5-alkoxy-tetrazolo[1,5-a]quinolinone compounds, a class of compounds represented by general formula I, their addition salts with pharmaceutically acceptable acids, and The invention relates to the use of the compounds and their addition salts with pharmaceutically acceptable acids as antidepressants.

Description

5-Alkoxy-tetrazolo[1,5-a]quinolinone derivatives and pharmaceutically acceptable salts thereof as antidepressants

technical field

The present invention relates to 5-alkoxy-tetrazolo[1,5-a]quinolinone derivatives, their addition salts with pharmaceutically acceptable acids, their preparation methods and their use in the preparation of antidepressants and containing their pharmaceutical compositions.

Background technique

Depression is the main type of affective disorder (Mood Disorder), which is a syndrome characterized by significant and persistent low mood. With the fast-paced and mental and psychological pressure brought by the market economy, the incidence of depression has increased significantly. According to a survey by the World Psychiatric Association, the global incidence of depression is 4.2%, and it reaches 6.9% in China, and the number of patients with depression is increasing at an annual growth rate of 113%. According to statistics, the cost of absenteeism, loss of work ability, treatment and rehabilitation caused by patients with depression in my country reaches hundreds of billions of yuan a year. Depression has become a recognized medical and sociological problem, which has attracted extensive attention from governments and relevant researchers. However, about one-third of the depressed patients in the world do not respond well to clinically used antidepressants, and the toxic side effects are obvious after long-term use of these antidepressants. In order to improve the therapeutic effect and eliminate or reduce side effects, antidepressants with new structural features and new mechanisms of action have increasingly become the targets of efforts in medical treatment, pharmacy, and scientific research.

Contents of the invention

In order to solve the deficiencies of the above problems, the present invention provides a new mechanism of action and a new 5-alkoxy-tetrazolo[1,5-a]quinone that exhibits valuable pharmacological properties as an antidepressant Phenone derivatives, their addition salts with pharmaceutically acceptable acids, their preparation methods and their use in the preparation of antidepressants, and pharmaceutical compositions containing them.

The present invention is realized in the following manner. The present invention provides compounds represented by the general formula I and their addition salts with pharmaceutically acceptable acids:

Wherein, R is selected from:

Methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-dodecyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 4-bromobenzyl, 4-methylbenzyl.

Among the pharmaceutically acceptable acids there may be mentioned, without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, citric acid, methanesulfonic acid.

The following compounds represented by general formula I of the present invention are preferably:

5-(2-fluorobenzyloxy)-tetrazolo[1,5-a]quinolinone

The method for preparing the compound represented by general formula I of the present invention, the method is starting material with general formula II:

Compound (II) reacts with bromoalkane or substituted benzyl chloride to obtain 4-alkoxyquinolinone, and then undergoes chlorination and ring reaction to obtain the compound represented by general formula I.

The present invention also includes a pharmaceutical composition, which includes any compound represented by general formula I, any compound in the addition salt thereof with a pharmaceutically acceptable acid, and at least one pharmaceutically acceptable excipient.

The pharmaceutically acceptable excipients are inert and non-toxic excipients. Among the pharmaceutical compositions according to the invention, particular mention may be made of those tablets or sugar-coated tablets, sublingual tablets, gelatin capsules, suppositories, creams suitable for administration by the oral, parenteral (intravenous or subcutaneous) and intranasal routes formulations, ointments, gels for the skin, injectable formulations or drinkable suspensions, etc.

The above-mentioned pharmaceutical composition of the present invention is used for treating depression.

The compounds of the present invention possess antidepressant properties, making them useful as antidepressant compounds. The pharmacological experiment result (seeing table 1) of the novel compound (as compound 4k) synthesized by the present invention, its antidepressant activity (reducing immobility time in forced swimming test) is better than listed antidepressant fluorine under 30mg/kg dose Xiding. The activity of this compound is higher than that of fluoxetine, the antidepressant with the highest annual sales in the world, indicating that it has the potential to be developed as an antidepressant.

Table 1. Results of forced swimming test (i.p.) of antidepressant pharmacological models

Data represent mean ± standard deviation (n = 6)

Compared with the blank group **p<0.01

Detailed ways

The specific examples given below are intended to further illustrate the preparation methods of the compounds of the present invention, but not to limit the scope of the compounds exemplified, that is to say that the compounds of formula I can be easily prepared by the methods described in these examples . Interchanges or modifications, as well as the use of necessary intermediates and solvents, are readily apparent to a chemist of ordinary skill.

Example 1: 4-(2-fluorobenzyloxy)quinolin-2(1H)-one

To 1.00g (6.2mmol) 4-hydroxyquinolin-2-one (II), 1.71g K ₂ CO ₃ (12.4mmol) and 6.2mmol 2-fluorobenzyl chloride, add 50ml DMF, stir at 80°C for 6 Hour. After the reaction, the reaction solution was poured into 200ml of ice water, filtered under reduced pressure, washed with water and dried to obtain 4-(2-fluorobenzyloxy)quinolin-2(1H)-one.

Example 2: 4-(2-fluorobenzyloxy)-2-chloroquinoline

Add an appropriate amount of POCl ₃ (as a solvent) to 5 mmol of 4-(2-fluorobenzyloxy)quinolin-2(1H)-one and 5 mmol of triethylamine, and stir at 80°C for 3 hours. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the residue was dissolved in 40 ml of dichloromethane, and washed with water and saturated brine in sequence. The dichloromethane layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 4-(2-fluorobenzyloxy)-2-chloroquinoline.

Example 3: 5-(2-fluorobenzyloxy)-tetrazolo[1,5-a]quinolinone

To 5 mmol of 4-(2-fluorobenzyloxy)-2-chloroquinoline and 7.5 mmol of sodium azide was added 50 ml of dimethylsulfoxide. The mixture was stirred at 60°C for 20 hours. Pour into water, suction filter and wash with water to obtain a solid, and then recrystallize from ethyl acetate to obtain 5-(2-fluorobenzyloxy)-tetrazolo[1,5-a]quinolinone. Melting point 267-269°C; yield 78.4%. ¹ H-NMR (CDCl ₃ , 300MHz): δ5.36(s, 2H, OCH ₂ ), 7.16(s, 1H, CH=), 7.19-7.37(m , 4H, Ar-H), 7.64-8.63 (m, 4H, Ar-H). IR (KBr) cm ^-1 : 1128, 1228 (COC), 1622 (C=N). MS (m/z): 295 (M+1). Anal. Calcd. for C16H11FN4O: C, 65.30; H, 3.77; N, 19.04. Found: C, 65.45; H, 3.89; N, 18.91.

All compounds provided herein were screened for antidepressant activity. The antidepressant activity of each compound was evaluated by measuring immobility time of mice by performing forced swimming test on mice. See R. D. Porsolt, A. Bertin, M. Jalfre, Arch. Int. Pharmacodyn. Ther. 229 (1977) 327-336.

The pharmaceutical composition can be carried out according to the following scheme:

Formulation for 1000 tablets each containing 100 mg of active ingredient:

6-(4-Chlorophenoxy)-tetrazolo[5,1-a]phthalazine----------------v---------- ---100g

Hydroxypropyl Cellulose --------------------------------------------- ---------2g

wheat starch------------------------------------------------ ---------10g

lactose------------------------------------------------- -----------100g

Magnesium stearate---------------------------------------------- -----------3g

talc------------------------------------------------- -------------3g

The dosage used should be adapted to the nature and severity of the disease, the route of administration and the age and weight of the patient. The daily dose varies between 0.01mg-1g, and can be administered once or in fractions.

The above description is only a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Different embodiments can be realized with some modifications within the range shown in the claims and the description and the accompanying drawings, which are intended to belong to the scope of the present invention.

Claims (4)

1. Compounds represented by general formula I, their addition salts with pharmaceutically acceptable acids:

Wherein, R is selected from: Methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-dodecyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 4-bromobenzyl, 4-methylbenzyl. 2. The compound represented by general formula I according to claim 1, its addition salt with a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid comprises: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, lemon acid, methanesulfonic acid. 3. The compound represented by general formula I according to claim 1 is: 5-methoxy-tetrazolo[1,5-a]quinolinone; 5-Ethoxy-tetrazolo[1,5-a]quinolinone; 5-propoxy-tetrazolo[1,5-a]quinolinone; 5-butoxy-tetrazolo[1,5-a]quinolinone; 5-pentyloxy-tetrazolo[1,5-a]quinolinone; 5-hexyloxy-tetrazolo[1,5-a]quinolinone; 5-heptyloxy-tetrazolo[1,5-a]quinolinone; 5-octyloxy-tetrazolo[1,5-a]quinolinone; 5-Dodecyloxy-tetrazolo[1,5-a]quinolinone; 5-benzyloxy-tetrazolo[1,5-a]quinolinone; 5-(2-fluorobenzyloxy)-tetrazolo[1,5-a]quinolinone; 5-(3-fluorobenzyloxy)-tetrazolo[1,5-a]quinolinone; 5-(4-fluorobenzyloxy)-tetrazolo[1,5-a]quinolinone; 5-(2-chlorobenzyloxy)-tetrazolo[1,5-a]quinolinone; 5-(3-chlorobenzyloxy)-tetrazolo[1,5-a]quinolinone; 5-(4-chlorobenzyloxy)-tetrazolo[1,5-a]quinolinone; 5-(2-Bromobenzyloxy)-tetrazolo[1,5-a]quinolinone; 5-(4-Bromobenzyloxy)-tetrazolo[1,5-a]quinolinone; 5-(4-methyloxybenzyl)-tetrazolo[1,5-a]quinolinone. 4. according to the purposes of the pharmaceutical composition of claim 1 in the preparation antidepressant medicine.