Depression and anxiety disorders constitute main psychiatric diseases. It is assumed that the lifetime prevalence of depression and anxiety disorders has been steadily increased in recent years. To date, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin and noradrenaline reuptake inhibitors (SNRI) and the like based on the monoamine hypothesis have been developed as antidepressants. Benzodiazepines based on the γ-aminobutyric acid mechanism (GABA) have been used as anxiolytics. In recent years, SSRI and SNRI have been demonstrated to be also effective for anxiety disorders such as panic disorder and obsessive-compulsive disorder for which benzodiazepines are not effective, and they are also the first-line treatments for anxiety disorders. However, SSRI and SNRI are not effective in patients with treatment-refractory depression and need to be taken for several weeks for the onset of antidepressive and anxiolytic effects, for example, disadvantageously. Accordingly, it is desirable to develop an antidepressant and anxiolytic based on a mechanism of action differing from that of an existing drug.
Melanin-concentrating hormone (MCH), a neuropeptide, consisting of 19 amino acids is biosynthesized and widely distributed in the limbic system and the like in the brain. The melanin-concentrating hormone-1 receptor (MCH1R) and the melanin-concentrating hormone-2 receptor (MCH2R) have been already known as two MCH receptor subtypes. MCH2R is not expressed in rodents and its physiological functions have not yet been elucidated; however, it has been elucidated that MCH1R is deeply associated with eating behavior and energy metabolism. More specifically, there is a report that food intake increases by injection of MCH to a rat. There is another report that a decrease of body-weight and an increase of metabolism are observed in MCH-defective gene-modified mice (see NON-PATENT DOCUMENT 1). Accordingly, an MCH1R antagonist may be possibly used as a prophylactic or therapeutic drug for obesity, eating disorder, appetite disorder, hyperphagia, bulimia, cibophobia, etc.
On the other hand, it is reported that MCH1R is also deeply involved in regulation of stress response and emotion. Activation of the hypothalamus-pituitary-adrenal (HPA) axis by MCH is antagonized by an MCH1R antagonist and a neutralizing antibody against corticotropin-releasing factor (CRF). MCH is presumed to activate the HPA system through facilitation of release of CRF from the hypothalamus. MCH1R is predominantly distributed in the accumbens involved in motivation and reward. When MCH is injected into this site, depressive-like symptoms are observed in a forced swimming test, whereas MCH knockout mice have antidepressive-like symptoms. A study using MCH1R knockout mice shows that MCH1R negatively regulates the activity of dopaminergic neurons involved in reward in the accumbens. Moreover, ATC0175, a nonpeptidic MCH1R antagonist, has antidepressive-like and anxiolytic-like effects in experimental animal models (NON-PATENT DOCUMENT 2). From the above facts, it is suggested that MCH1R is involved not only in control of eating behavior and energy metabolism but also in onset of depression and anxiety, and it can be expected that an MCH receptor antagonist, in particular, an MCH1R antagonist, may be an antidepressant and anxiolytic having a mechanism of action differing from that of a conventional one.
Recently, MCH receptor antagonists having a naphthalene skeleton and a 1,3-benzodioxole skeleton are disclosed in PATENT DOCUMENT 1 and NON-PATENT DOCUMENTs 3, 4, 5 and 6. However, these documents neither disclose nor suggest the structure of a compound according to the present invention.    PATENT DOCUMENT 1: U.S. Patent Application Publication No. 2005/209274    NON-PATENT DOCUMENT 1: Trends Endocrinol Metab vol. 11, p. 299-303 (2000)    NON-PATENT DOCUMENT 2: Drug Development Research vol. 65, p. 278-290 (2005)    NON-PATENT DOCUMENT 3: 224th The American Chemical Society MEDI-343 (2002)    NON-PATENT DOCUMENT 4: Bioorganic & Medicinal Chemistry Letters vol. 16, p. 5445-5450 (2006)    NON-PATENT DOCUMENT 5: Bioorganic & Medicinal Chemistry Letters vol. 15, p. 3412-3416 (2005)    NON-PATENT DOCUMENT 6: Bioorganic & Medicinal Chemistry Letters vol. 17, p. 874-878 (2007)
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