阅读说明：本技术 沃替西汀衍生物、制备方法及其药物用途 (Vortioxetine derivatives, preparation method and pharmaceutical application thereof ) 是由 王仲清 林碧悦 李英龙 寇景平 黄芳芳 于 2019-09-27 设计创作，主要内容包括：本发明提供下式所示的化合物,其中R<Sub>1</Sub>和R<Sub>2</Sub>分别为独立选自氢或1-20个碳原子的碳链,n为0或1；以及制备上述的化合物的方法；本发明还提供上述的化合物在制备用于治疗重度抑郁症的药物中的应用,上述的化合物在体内能够缓慢地水解为沃替西汀,延长药物在体内的发挥药效的持续时间,由此减少用药次数。<Image he="595" wi="363" file="DDA0002218467690000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides compounds of the formula wherein R 1 And R 2 Are independently selected from hydrogen or carbon chains of 1-20 carbon atoms, and n is 0 or 1; and processes for preparing the above compounds; the invention also provides application of the compound in preparing a medicament for treating major depressive disorder, wherein the compound can be slowly hydrolyzed into vortioxetine in vivo, and the duration of the drug effect of the medicament in vivo is prolonged, so that the administration frequency is reduced.)

1. A compound represented by the formula (I):

wherein the content of the first and second substances,

R₁、R₂are independently selected from hydrogen or carbon chains of 1-20 carbon atoms, and n is 0 or 1.

2. The compound or salt thereof according to claim 1, wherein the compound has a chemical structure represented by the following structural formula:

wherein R is₁、R₂Are independently selected from carbon chains of 1-10 carbon atoms, and n is 0 or 1;

alternatively, the first and second electrodes may be,

3. a process for the preparation of a compound of formula (V), which comprises reacting a compound of formula (III) with a compound of formula (IV) in a solvent in the presence of magnesium tert-butoxide, and after the reaction, subjecting to a post-treatment to obtain a compound of formula (V):

wherein the content of the first and second substances,

R₁、R₂each independently selected from carbon chains of 1 to 20 carbon atoms;

the solvent for the reaction is at least one selected from dichloromethane, acetonitrile, ethyl acetate, toluene or N' N-dimethylformamide;

the reaction time is 1-11 h; or the reaction time is 3-9 h; or the reaction time is 5-7 h;

the reaction temperature of the reaction is 30-100 ℃; or the reaction temperature is 40-90 ℃; or the reaction temperature is 50-80 ℃; or the reaction temperature is 60-70 ℃;

the feeding molar ratio of the compound shown in the formula (III) to the magnesium tert-butoxide is 1: 0.8-1: 1.8; or the feeding molar ratio of the compound shown as the formula (III) to the magnesium tert-butoxide is 1: 1-1: 1.6; or the feeding molar ratio of the compound shown as the formula (III) to the magnesium tert-butoxide is 1: 1.2-1: 1.4;

the feeding molar ratio of the compound of the formula (III) to the compound of the formula (IV) is 1: 1.3-1: 2.3; or the feeding molar ratio of the compound shown in the formula (III) to the compound shown in the formula (IV) is 1: 1.5-1: 2.1; or the feeding molar ratio of the compound shown in the formula (III) to the compound shown in the formula (IV) is 1: 1.7-1: 1.9.

4. the method of claim 3, wherein the post-processing comprises: cooling to 20-60 ℃, adding acetic acid, stirring, concentrating and evaporating the solvent, adding water, extracting with dichloromethane, washing with water, separating liquid, and concentrating dichloromethane.

5. A process for the preparation of a compound of formula (VI), which comprises reacting a compound of formula (V) with trimethylbromosilane, after completion of the reaction, to obtain a compound of formula (VI):

wherein the content of the first and second substances,

R₁and R₂Each independently selected from carbon chains of 1 to 20 carbon atoms;

the solvent for the reaction is at least one selected from dichloromethane, acetonitrile, ethyl acetate, toluene or N' N-dimethylformamide;

the reaction time is 1-7 h; or the reaction time is 2-6 h; or the reaction time is 3-5 h;

the reaction temperature of the reaction is 30-130 ℃; or the reaction temperature is 50-110 ℃; or the reaction temperature is 60-100 ℃; or

The reaction temperature is 70-90 ℃;

the feeding molar ratio of the compound shown in the formula (V) to the trimethyl bromosilane is as follows: 1: 2.5-1: 3.5; or the feeding molar ratio of the compound shown in the formula (V) to the trimethyl bromosilane is as follows: 1: 2.7-1: 3.3; or the feeding molar ratio of the compound shown in the formula (V) to the trimethyl bromosilane is as follows: 1: 2.8-1: 3.3; or the feeding molar ratio of the compound shown in the formula (V) to the trimethyl bromosilane is as follows: 1: 2.9-1: 3.1.

6. the method of claim 5, the post-processing comprising: evaporating the solvent to dryness, adding methyl tert-butyl ether and pulping.

7. A process for the preparation of a compound of formula (XII), which comprises reacting a compound of formula (III) with a compound of formula (XI) in a solvent comprising elemental iodine, and after completion of the reaction, subjecting to a post-treatment to obtain a compound of formula (XII):

wherein the content of the first and second substances,

R₁、R₂are respectively and independently selected from carbon chains with 1 to 20 carbon atoms, and n is 0;

the solvent for the reaction is at least one selected from dichloromethane, toluene or N' N-dimethylformamide;

the reaction time is 3-13 h; or the reaction time is 5 to 12 hours; or the reaction time is 7-9 h;

the reaction temperature of the reaction is-10 ℃ to 40 ℃; or the reaction temperature is 0-30 ℃; or the reaction temperature is 10-20 ℃;

the feeding molar ratio of the elemental iodine to the compound of the formula (III) is 1: 1; or the feeding molar ratio of the elemental iodine to the compound shown in the formula (III) is 1: 2; or the feeding molar ratio of the elemental iodine to the compound shown in the formula (III) is 1: 3;

the feeding molar ratio of the compound of the formula (XI) to the compound of the formula (III) is 1: 1; or the feeding molar ratio of the compound of the formula (XI) to the compound of the formula (III) is 1: 2; or the feeding molar ratio of the compound of the formula (XI) to the compound of the formula (III) is 1: 3.

8. The method of claim 7, the post-processing comprising: adding water, adjusting the ph to be 2-4 by using dilute hydrochloric acid, adjusting the ph to be 6-8 by using a saturated sodium hydrogen carbonate aqueous solution, separating liquid, and concentrating an organic phase.

9. Use of any one of the compounds of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of major depressive disorder.

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to vortioxetine phosphate compounds or salts thereof, a preparation method of the vortioxetine phosphate compounds or the salts thereof, and application of the vortioxetine phosphate compounds or the salts thereof as medicines.

Background

Depression, also known as depressive disorder, is characterized clinically by a marked and persistent depression in the mood, the main type of mood disorder. Clinically, there are depressed mood, depression, and even pessimistic and boredom, suicide attempts or behaviors. In most cases, there is a tendency for recurrent episodes, with most of each episode remitting and some remaining symptoms or becoming chronic. Worldwide, the population affected by some form of depression accounts for 25% of all women, 10% of all men, and 5% of all teenagers. The cause of depression is not clear, at present, antidepressant has become the first treatment means for depression patients, and the selective serotonin (5-HT) reuptake inhibitor is mainly used clinically, so that the application is most extensive.

Vortioxetine (Vortioxetine) is a new drug marketed in 2013, mainly used for the treatment of major depression (MDD), the mechanism of action of which is not completely clear, but is generally considered to be related to 5-HT re-extraction inhibition, and is the first antidepressant drug with dual mechanisms of action including 5-HT receptor activation and reabsorption inhibition. The composition has safety data that are not inferior or superior to SSRIs (5-hydroxytryptamine reuptake inhibitors) and SNRIs (5-hydroxytryptamine and norepinephrine reuptake inhibitors), and better body weight control data. Vortioxetine is superior to agomelatine for patients who do not respond fully to SSRI/SNRI. The effect of treating depression is similar to duloxetine, and is better than venlafaxine and agomelatine, the safety is good, the effect is better than vilazodone, the risk of juvenile suicide tendency is increased, but the effectiveness and safety of vortioxetine are better than those of traditional SSRIs on the whole. Currently, vortioxetine only has different specifications of vortioxetine hydrobromide tablets for oral administration, the blood concentration of the vortioxetine tablet is short in maintenance time, the vortioxetine tablet needs to be administered every day (once a day), the frequent administration is needed, the non-compliance of a patient is increased, and the self-administration is difficult due to the mood fluctuation of the patient and the influence of other symptoms, so that the treatment failure is often caused.

No long-acting preparation of vortioxetine or a salt thereof, or a long-acting preparation of vortioxetine derivative or a salt thereof is currently on the market, and research on vortioxetine derivatives or salts thereof having a long-acting effect is lacked in the prior art.

In view of the defect that the vortioxetine hydrobromide tablet which is a commercially available preparation needs to be frequently administered when treating patients, the development of a vortioxetine phosphorus derivative or a salt of the derivative is urgently needed, the vortioxetine phosphorus derivative or the salt of the derivative can be slowly hydrolyzed in vivo into vortioxetine, the action time of the vortioxetine in vivo is prolonged, the administration frequency is reduced, and vortioxetine phosphate compounds or salts thereof have the potential.

Disclosure of Invention

Drawings

FIG. 1 shows a high performance liquid chromatography of the compound of formula (VII) prepared from example 1.

Figure 2 shows a high performance liquid chromatography of the compound of formula (VI) prepared from example 2.

Figure 3 shows a high performance liquid chromatography of the compound of formula (IX) prepared from example 3.

Figure 4 shows a high performance liquid chromatography of the compound of formula (X) prepared from example 4.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.