Cells show a wide variety of physiology in responding to extracellular stimuli such as neurotransmitter, hormone and a growth factor. A calcium ion plays an important role in this regard as a messenger of intracellular signaling. The main source of the calcium is the intracellular calcium store and extracellular liquid. Calcium is released from the intracellular calcium store via inositol 1,4,5-trisphosphate (IP3) receptor as the second messenger, or ryanodine receptor which is insensitive to IP3 but releases calcium along with the increase of the intracellular calcium concentration.
As the intracellular second messenger, IP3 carries out IP3-induced Ca release (IICR), i.e., induces the release of a calcium ion from the intracellular calcium ion pool. IP3 receptor is a channel for releasing the intracellular calcium ion, which is activated by the integration with IP3. The IP3 receptor forms a gene family, and is diverse in its function, tissue- or cell-specific expression and intracellular localization, and plays an essential important role in vital functions.
It is known that IP3 is produced in a pathway activating a various receptors coupled with G-protein activity or in a pathway activating a various receptors coupled with tyrosine kinase activity. Phospoholipase C, which was activated in the above pathway, decomposes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers, i.e., IP3 and diacylglycerol (DG). IP3 binds to an IP3 receptor existing in the intracellular calcium store and has calcium released. On the other hand, DG activates protein kinase C with the released calcium and controls various types of physiology.
It is known that a various channels are concerned with the influx of the calcium ion from the extracellular fluid. The channels can be divided broadly into a voltage-dependent channel which functions depending on the membrane potential and a channel which functions independently from the potential. As a channel of the latter, a neurotransmitter receptor having calcium permeabirelity (e.g., NMDA receptor) is known. Recently, attention has been drawn to a calcium permeability channel which functions by the activation of G-protein coupled receptor and tyrosine kinase type receptor, and receptor activated calcium channel (RACC). RACC includes a capacitative calcium entry (CCE) channel, second messenger operated channel and G-protein operated channel.
A CCE channel is activated by the release and depletion of calcium ion from the intracellular calcium store, and makes extracellular calcium ions flow and reload into the intracellular calcium store. From this, CCE channels are also called store operated channels (SOCs).
The presence of the channel is established electrophysiologically in nonexcitatory cells such as immunocytes, vascular endothelial cells and thrombocytes, and the channel is known as a main calicium entry pathway for the nonexcitatory cells. However, its molecular substance has not been made clear. Moreover, the mechanisms of the channel in recognition of the depletion of the intracellular calcium store and in activation are also uncertain.
However, from the following experiments and the like, the fact is verified that the capacitative calcium entry and the calcium release from the intracellular calcium store wherein the IP3 is concerned as mentioned above, play an important role in the expression of cell functions.
That is,    (1) When a thrombocyte is stimulated by thromboxane A2 and thrombin, IP3-mediated aggregation is caused and thrombus is formed, leading to ischemic diseases in hearts and brains.
On this occasion, it is known that the capacitative calcium entry consequent upon the IP3-induced Ca release (IICR) is essential to the thrombocyte aggregation (Biochimica et Biophysica Acta, 1082, 219–238 (1991); Platelets, 11(4), 215–21(2000)).    (2) Helper T (Th1) cells of the subset 1 in T-lymphocytes produce and secrete cytokines such as interleukin 2 (IL-2) and interferon γ and express IL-2 receptors. On this occasion, to start the transcription of the IL-2 genes, it is necessary for the NF-AT as a transcription promoter to become active and make transition to the nuclei. It is known that the increase of the intracellular calcium concentration owing to the capacitative calcium entry is essential for the activation of NF-AT (J. Cell Biol., 131(3), 655–67(1995)).    (3) IP3 produced by the stimuli of leukotriene D4 (LTD4) and angiotensin II causes calcium release, which makes bronchial smooth muscle and vascular smooth muscle contract, and causes asthma, hypertension, cerebrovascular spasm, etc. It is known that the capacitative calcium entry is essential on this occasion (J. Pharm. Exp. Ther., 244, 508–515 (1987); Protein Nucleic Acid Enzyme, 36, 885–895 (1991); J. Membr. Biol., 155(1), 61–73(1997)).    (4) In exocrine pancreatic cells, the intracellular calcium concentration increases via IP3 by stimuli of such as cholecystokinin and acetycholine, which causes abnormal secretion of protease and leads to pancreatitis. It is known that the capacitative calcium entry is essential on this occasion (Pharmacology & Toxicology, 68, 83–87 (1991); Proc. Natl. Acad. Sci. USA, 97(24), 13126–13131(2000)).    (5) Leukotriene B4 (LTB4) produced by neutrophils increases the intracellular calcium concentration via IP3, causes neutrophil migration to inflammation sites and exaggerates the inflammation (ANN. NY. ACAD. Sci., 524, 187–195 (1988)). In the myocardial infarction, production of LTB4 is also concernedwith the expansion of the necrotic layer (J. Pharm. Exp. Ther., 228, 510–522 (1983)).    (6) In kidneys, stimuli of such as angiotensin II and bradykinin increases mesangium cells together with the IP3 production, which causes a type of glomerulonephritis. IP3 is also concerned with other various renal diseases (Metabolism, 27, 413–425 (1990)).
Recently, the possibility has come into clear that the capacitative calcium entry takes an important function not only in the above nonexcitatory cells but also in nerve cells. For example, it is known that presenilin known as a gene causing familial Alzheimer's disease has a function as y-secretase which cuts amyloid protein precursor. When presenilin induced with point mutation discovered in the patient of familial Alzheimer's disease is expressed in cultured cells, it was proved that the capacitative calcium entry functions abnormally (Neuron, 27(3), 561–72(2000)). The experiment using the primary cultured cells derived from a mouse whose presenilin genes were destroyed also proved the abnormal function of the capacitative calcium entry (J. Cell Biol., 149(4), 793–8(2000)).
As mentioned above, the endogenous calcium and capacitative calcium entry are deeply linked to various diseases.
Accordingly, as an endogenous calcium release inhibitor or a capacitative calcium entry inhibitor has a function inhibiting the increase of the intracellular calcium concentration, it is deemed to be useful as an agent for the prophylaxis and/or treatment of platelet aggregation, immune deficiency diseases, allergosis, ischemic diseases in hearts and brains, bronchial asthma, hypertension, cerebrovascular spasm, various renal diseases, pancreatitis, Alzheimer's disease, etc.
The specification of Japanese Patent No. 2987727 discloses that 2-aminoethyl diphenylborinate and tetraphenylboroxane(tetraphenyldiboroxide) having an inhibitory effect on calcium release from the endogenous calcium store by the mechanisms of IP3-induced Ca release (IICR) and calcium induced Ca release (CICR).

Also, it is described that 2-aminoethyl diphenylborinate has an inhibitory action on SOCs through an inhibitory action on IP3 receptors (Science, 287, 1647–1651(2000)).
Moreover, the specification of WO02/38140 describes that bis-1-oxaquinolizidine, xestospongin C, xestospongin A, Araguspongin B and the like are useful as an inhibitor of calcium channels mediated by IP3 receptors.
However, pharmaceutical agents have not yet been found for prophylaxis and/or treatment of various diseases by decreasing the concentration of the intracellular calcium which has been abnormally increased by the activation of IP3 receptors or capacitative calcium entry.