JP-7857315-B2 - Antidepressant and anti-anxiety substituted cinnamamide compounds

Inventors

• マー，シアオフイ
• ガオ，シューコン
• ワン，シアンヤン
• リー，シアオチン
• リウ，ルイ
• ジョウ，シュイピン

Assignees

• 天士力医薬集団股分有限公司

Dates

Publication Date

20260512

Application Date

20220524

Priority Date

20210528

Claims (11)

1. The following structural formula: A substituted cinnamamide compound represented by [formula].
2. The following structural formula: Antidepressant and anti-anxiety compounds as indicated by [this symbol].
3. The compound according to claim 1 or 2, characterized by existing in the form of a solvate.
4. The compound according to claim 1 or 2, characterized in that it exists in the form of a pharmaceutically acceptable salt.
5. A pharmaceutical composition containing the compound described in claim 1.
6. The pharmaceutical composition according to claim 5, which exists in any administerable pharmaceutical form, and which is selectively selected from tablets, capsules, oral solutions, buccal preparations, granules, pills, powders, ointments, erythematous preparations, suspensions, powders, solutions, injections, suppositories, ointments, hard ointments, creams, sprays, drops, and patches, wherein the tablets are selectively sugar-coated tablets, film-coated tablets, or enteric-coated tablets, the capsules are selectively hard capsules or soft capsules, and the injections are selectively one of injection solutions, lyophilized powder injections, and liquid injections.
7. The pharmaceutical composition according to claim 5, which is used in combination with other antidepressants or anxiolytics, or further comprises other antidepressants or anxiolytics, the other antidepressants or anxiolytics being selected from nefazodone, sulpiride, alprazolam, lorazepam, buspirone, tandospirone, methylphenidate, fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine, reboxetine, venlafaxine, flupentixol, melitracene, and neurostane.
8. A method for producing the compound according to claim 1 or 2, comprising reacting (E)-3-(3',4'-methylenedioxy-5'-trifluoromethylphenyl)-acrylic acid (i.e., intermediate A) with NH3 to obtain compound M2.
9. The reaction pathway is as follows: A method for producing the compound according to claim 8, including the method described above.
10. The manufacturing method according to claim 9, comprising the steps of: dissolving (E)-3-(3',4'-methylenedioxy-5'-trifluoromethylphenyl)-acrylic acid (intermediate A) in dichloromethane, adding a catalytic amount of N,N-dimethylformamide, adding oxalyl chloride dropwise under an ice bath, stirring at room temperature until the reaction of the starting materials is complete, concentrating and drying the reaction solution, adding dichloromethane to dissolve it, adding aqueous ammonia dropwise under an ice bath, reacting at room temperature until the reaction is complete, removing the solvent under reduced pressure, adjusting the acidity by adding dilute hydrochloric acid, precipitating the solid, filtering and washing to obtain the crude product, purifying it by silica gel column chromatography to obtain M2.
11. Use of the compound according to claim 1 or 2, or the pharmaceutical composition according to any one of claims 5 to 7, in the manufacture of an antidepressant, an anxiolytic, or an antidepressant/anxiolytic.

Description

This application claims priority to the Chinese invention patent application filed on May 28, 2021, with the title of "Novel Compounds for Antidepressant and Anxiolytic Effects" and application number 202110606431.2, the entire contents of said Chinese patent application are incorporated herein by reference. This application relates to pharmaceutical compounds, but is not limited to them; in particular, it relates to novel substituted cinnamamide compounds with antidepressant and anxiolytic properties. Depression and anxiety disorders are major illnesses that harm people's mental health, and with the accelerating pace of modern life, the number of people suffering from them is increasing year by year. Recent statistics show that the number of people suffering from various types of depression in China has reached 26 million, with a relatively large proportion of them being adolescents. Therefore, research and development of antidepressants and anti-anxiety drugs has significant economic and social benefits. Extensive research has shown that alterations in central monoamine neurotransmitters, dopamine, cholinergic activity, corresponding receptor function changes, and neuroendocrine dysfunction may play a significant role in the onset and progression of this disease. Therefore, the treatment principle should focus on regulating the hypothalamic monoamine neurotransmitter content and their receptor function, as well as restoring normal neuroendocrine function. Currently, the primary treatment for depression and anxiety disorders remains medication. Traditionally, antidepressants and anxiolytics used clinically have mainly consisted of chemical drugs such as tricyclic antidepressants, benzodiazepines, 5-hydroxytryptamine reuptake inhibitors, and monoamine oxidase inhibitors. While these drugs have some therapeutic effect on depression and anxiety disorders, they also have drawbacks, including relatively high toxicity and side effects. Monoamine oxidase inhibitors, in particular, cause toxic liver damage due to their selectivity and irreversible inhibition of the enzyme, thus exhibiting some toxicity and side effects. Common tricyclic antidepressants include doxepin, amitriptyline, and clomipramine. These drugs are relatively effective against endogenous depression, achieving a therapeutic effect of over 80% in cases of despondency, loss of interest, and pessimism, but they have strong cardiotoxicity, resulting in a relatively high incidence of adverse reactions. Selective 5-HT reuptake inhibitors (SSRIs) are novel antidepressants and anxiolytics that emerged in the late 1980s. They maintain the antidepressant and anxiolytic effects of conventional drugs while significantly reducing adverse reactions to other receptors, and have become the standard first-line treatment in Western countries. Examples of commonly used SSRIs include fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine. Due to gastrointestinal absorption and hepatic metabolism, gastrointestinal dysfunction and sexual dysfunction can occur, affecting long-term use to some extent. Furthermore, conventional antidepressants and anxiolytics have a slow onset of action (6-8 weeks or more), and are only effective in about 30% of patients. Therefore, in the treatment of severe depression, there is an urgent need for drugs with a rapid onset of action (especially in patients with suicidal tendencies), relatively good therapeutic efficacy, relatively low toxicity and side effects, and a novel mechanism of action. Chinese patents CN102850317A (application number 201210123842.7, hereinafter abbreviated as "Patent A") and CN103687850A (application number 201280020049.2, hereinafter abbreviated as "Patent B") disclose substituted cinnamamide derivatives, methods for producing them, and their use as therapeutic and preventive drugs for mental disorders such as depression. Thirteen specific compounds, I-1 to I-13, are disclosed. In these patents, mouse tail suspension tests, "acquired despair" depression model experiments, anti-reserpine ptosis depression model experiments, and mouse forced swimming tests have verified that administration of 10 mg/kg of compounds I-5, I-9, I-10, I-11, I-12, and I-13 for 7 days can significantly shorten the mouse tail suspension immobility time. Seven consecutive days of administration of compounds I-4, I-5, I-10, I-11, I-12, and I-13 at a dose of 10 mg/kg significantly antagonized the reserpine-induced hypothermia and immobility in mice and improved the degree of eye closure, indicating a certain modulatory effect on the re-ingestion of 5-HT, NE, and DA. Compounds I-5, I-10, and I-13 all significantly shortened the immobility time during forced swimming in mice, and the effect of I-5 on the immobility time during forced swimming in mice showed a certain dose-dependent relationship. Among these, I-5, which showed the best effect, is currently in clinical research. Chinese Patent CN107011313A (Application No. 201710038281.