Depression is a syndrome characterized by significant and lasting low mood, which mainly manifests as affective disorder. The symptoms include low mood, less speech, slow mentality and motion, and even suicide attempt. Depression, as a chronic mental disease, has become a fiendish problem which bothers the medical health service in China, due to long treatment course, slow effect onset and higher rate of relapse, disability and suicide. According to “World Health Reports” announced by World Health Organization (WHO), depression has become the fourth largest disease in the world, and depression might become the second largest illness after heart disease in 2020, and thus become a serious problem to human health.
So far, the action mechanism of antidepressant has not been clearly demonstrated. Drugs having definite effect substantially act on synapses of the nerve ending, and exert their curative effects by adjusting the level of neurotransmitters in synaptic cleft. The biochemistry study on etiology indicated that depression relates mainly to five types of neurotransmitters, i.e., central 5-hydroxytryptamine (5-HT), noradrenaline (NA), dopamine (DA), acetylcholine (Ach), and γ-aminobutyric acid (GABA).
Antidepressant can be divided into two categories: early non-selective antidepressants and novel selective reuptake inhibitors. Non-selective antidepressants mainly include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs); selective reuptake inhibitors mainly comprise selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs), noradrenaline (NA) reuptake inhibitors (NRIs), noradrenergic and specific 5-HT reuptake inhibitors (NDRIs), 5-HT and NA dual reuptake inhibitors (SNRIs), 5-HT re-absorption enhancers, and the like.
Early monoamine oxidase inhibitors and tricyclic antidepressants have serious adverse reactions; as for the subsequent selective NA reuptake inhibitors and selective 5-HT reuptake inhibitors, although they have less adverse reactions, disadvantages such as slow onset, indefinite efficacy and the like, still exist. Therefore, the effects of all kinds of drugs above in treating depression are not satisfactory. So far, the existing antidepressants still can not meet the demand of clinical treatment.
Venlafaxine, the first 5-HT and NA dual reuptake inhibitor marketed in American in 1997, and dutoxetine marketed in 2004 have advantages of rapid onset of action, compared with selective 5-hydroxytryptamine reuptake inhibitors such as fluoxetine, and noradrenaline reuptake inhibitors such as reboxetine, and have significant effects on both serious depression and refractory depression. From venlafaxine on, development on the novel antidepressants that have 5-HT and NA dual action routes, faster onset, fewer side effects and stronger effect, becomes the research emphasis and an important development direction.
At present, many studies indicate that the addition of DA reuptake inhibitors in dual reuptake inhibitors can obtain better antidepression effect. 5-HT, NA and DA triple selective reuptake inhibitors (also known as “broad-spectrum” antidepressants), developed based on dual reuptake inhibitors, are now still in clinical research phase. For example, triple selective reuptake inhibitor DOV-216303 developed by DOV Pharmaceutical Inc. is in phase III clinical trial; NS-2359 developed jointly by GlaxoSmithKline and NeuroSearch Inc. is now in phase II clinical trial of antidepressant. These monoamine transmitter triple selective reuptake inhibitors possess advantages of high effectiveness and fast onset and are becoming hot points in the antidepressants development.
The applicant has disclosed aryl alkanol piperazine derivatives and their use in preparation of antidepressants in Chinese patent ZL02111934.1. A preferred compound therein, N1-benzyl-N4-[1-methyl-2-(5′-chloro-6′-methoxyl-2′-naphthyl) hydroxyethyl]piperazine (IV-19, SIPIyy24, see formula A below), has a dual inhibition effect on the reuptake of 5-HT and NA, and has a strong antidepression biologic activity on animals. But a further research finds that the antidepression effect thereof is still not so satisfactory and adverse reaction thereof is obvious.

Subsequently, the applicant disclosed the optical isomers of compound SIPIyy24 and the use thereof in Chinese patent ZL 200510030354.1. Study shows that the (1S,2R) optical isomer of SIPIyy24 (code SIPI5286) has an inhibition effect on the reuptake of the three kinds of monamine transmitters, i.e. 5-HT, NA and DA. It is a novel triple reuptake inhibitor, and has better antidepression activity and safety than that of the racemate, and is worthy of being a novel antidepressant. However, it is found through further studies that, the half life of SIPI5286 is too short, and thus not suitable to be formulated into a medicament.