Histamine is usually stored within intracellular granules in mast cells, lung, liver and gastric mucosa, etc. In response to external stimuli such as antigen binding to cell surface antibody, histamine is released into the extracellular environment. For example, when mast cells are stimulated by an antigen entering from outside, histamine is released from the mast cells and stimulates histamine H1 (H1) receptors located on blood vessels or smooth muscle to cause allergic reactions. Likewise, histamine released from ECL cells (enterochromaffin-like cells) on the gastric mucosa stimulates histamine H2 (H2) receptors on the parietal cells to promote gastric acid secretion. Based on these facts, H1 and H2 receptor antagonists have been developed as therapeutic agents for allergic diseases and gastric ulcer, respectively, both of which are now used widely as medicaments.
Further, it has been elucidated that histamine serves as a neurotransmitter and acts on the third histamine receptor (histamine H3 (H3) receptor) located in central and peripheral nerves to thereby exert various physiological functions. This receptor was cloned in 1999 and determined for its gene sequence and amino acid sequence. However, its amino acid sequence homology was as low as 22% and 21.4% with H1 receptor and H2 receptor, respectively (see Non-patent Document 1). H3 receptors are present in the presynaptic membrane and are shown to serve as autoreceptors controlling the synthesis and release of histamine (see Non-patent Document 2). Moreover, H3 receptors are also shown to control not only the release of histamine, but also the release of other neurotransmitters including acetylcholine, serotonin, dopamine and noradrenaline (see Non-patent Document 3). It is also suggested that H3 receptors would be active in the absence of agonists, and their activity can be inhibited by compounds serving as inverse agonists. These facts suggest that H3 receptor antagonists or inverse agonists would enhance the release of H3 receptor-regulated neurotransmitters and may serve as therapeutic agents for various diseases related to abnormal release of these neurotransmitters.
Experiments in animal models indicate a possibility that H3 receptor antagonists or inverse agonists can be used as therapeutic agents for dementia, Alzheimer's disease (see Non-patent Documents 4 and 5), attention-deficit hyperactivity disorder (see Non-patent Document 6), schizophrenia (see Non-patent Document 7), epilepsy, central convulsion, etc.
Moreover, it is shown that H3 receptors are involved in eating behavior (see Non-patent Document 8); and hence possible target diseases for H3 receptor antagonists or inverse agonists also include metabolic diseases such as eating disorders, obesity, diabetes, hyperlipidemia, etc.
Further, it is shown that histamine regulates the circadian rhythm in the brain and is responsible for maintaining a balance between waking and sleeping states (see Non-patent Documents 9 and 10); and hence possible target diseases for H3 receptor antagonists or inverse agonists also include sleep disorders and diseases associated with sleep disorders such as narcolepsy, sleep apnea syndrome, circadian rhythm disorder, depression, etc.
Furthermore, it is shown that H3 receptors are present in sympathetic nerves on the nasal mucosa, and there is a report showing that the combined use of H3 and H1 receptor antagonists remarkably improves nasal congestion (see Non-patent Document 11). This indicates a possibility that H3 receptor antagonists or inverse agonists are useful for treatment of allergic rhinitis or other diseases, either alone or in combination with H1 receptor antagonists.
H3 receptor antagonists or inverse agonists have been summarized in several reviews (see Non-patent Documents 12 to 15), and reference may be made to these reviews. In the early years, many reports were issued for imidazole compounds starting from histamine itself as a leading compound. However, these compounds have not yet been developed as medicaments because they are feared to have negative effects such as inhibition of a drug-metabolizing enzyme, cytochrome P450 (CYP).
In recent years, many reports have been issued for non-imidazole H3 receptor antagonists or inverse agonists (see Patent Documents 1 to 15). However, there is no report about compounds having the structure disclosed in the present invention.    Patent Document 1: International Patent Publication No. WO2002/012190    Patent Document 2: International Patent Publication No. WO2002/040461    Patent Document 3: International Patent Publication No. WO2005/007644    Patent Document 4: International Patent Publication No. WO2005/097751    Patent Document 5: International Patent Publication No. WO2005/097778    Patent Document 6: International Patent Publication No. WO2005/118547    Patent Document 7: International Patent Publication No. WO2006/014136    Patent Document 8: International Patent Publication No. WO2006/023462    Patent Document 9: International Patent Publication No. WO2006/045416    Patent Document 10: International Patent Publication No. WO2006/046131    Patent Document 11: International Patent Publication No. WO2006/059778    Patent Document 12: International Patent Publication No. WO2006/061193    Patent Document 13: International Patent Publication No. WO2006/107661    Patent Document 14: International Patent Publication No. WO2006/103057    Patent Document 15: International Patent Publication No. WO2007/094962    Non-patent Document 1: Lovenberg T. W. et al., Molecular pharmacology, 55, 1101-1107, 1999    Non-patent Document 2: Arrang J-M. et al., Nature, 302, 832-837, 1983    Non-patent Document 3: Brown R. E. et al., Progress in Neurobiology, 63, 637-672, 2001    Non-patent Document 4: Huang Y-W. et al., Behavioural Brain Research, 151, 287-293, 2004    Non-patent Document 5: Komater V. A. et al., Behavioural Brain Research, 159, 295-300, 2005    Non-patent Document 6: Passani M. B. et al., Neuroscience and Biobehavioral Reviews, 24, 107-113, 2000    Non-patent Document 7: Fox G. B. et al., J. Pharmacol. Exp. Ther., 313, 176-190,    Non-patent Document 8: Hancock A. A. et al., Curr. Opin. Investig. Drug, 4, 1190-1197    Non-patent Document 9: Huang Z-L. et al., Prog. Natr. Acad. Sci., 103, 4687-4692, 2006    Non-patent Document 10: Babier A. J. et al., Br. J. Pharmacol., 143, 649-661, 2004    Non-patent Document 11: McLeod R. L. et al., Am. J. Rhinol., 13, 391-399, 1999    Non-patent Document 12: Schwartz J. C. et al., Trends in Pharmacol. Sci., 7, 24-28, 1986    Non-patent Document 13: Passani M. B. et al., Trends in Pharmacol. Sci., 25, 618-625, 2004    Non-patent Document 14: Leurs R. et al., Nature Drug Discovery, 4, 107-122, 2005    Non-patent Document 15: Leurs R. et al., Drug Discovery Today, 10, 1613-1627, 2005
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