(a) Field of the Invention
2-Imino-1,3-thiazoline-based compounds represented by the following Chemical Formula I, and T-type calcium channel inhibitors containing the compound are provided. The T-type calcium channel inhibitors according to the present invention are useful as a treating agent of diseases associated with over-expression of T-type calcium channel.

(b) Description of the Related Art
The T-type calcium channel is a kind of voltage-dependent calcium channel, and plays an important role in regulating the intracellular calcium level at depolarization. As coding genes for the voltage-dependent calcium channels, ten (10) genes have been found, which may be classified into two (2) families of a high voltage activated (HVA) family and a low voltage activated (LVA) family according to the intensity of the activating voltage. The voltage-dependent calcium channels may be classified into three (3) families of L-type channels (Cav1), P/Q-type and N-type (nervous unit) channels (Cav2), and T-type channels, wherein the L-type channels and the P/Q-type and N-type channels belong to the high voltage activated family, and the T-type channels belong to the low voltage activated family (Ertel et al., 2000).
The T-type calcium channel is characterized by a low-voltage activated calcium current, rapid activation, and slow inactivation. Thus far, as coding genes for the T-type calcium channel, three (3) genes have been identified, and they are called α1G (Cav3.1), α1H (Cav3.2), and α1I (Cav3.3), respectively (Cribbs et al., 1998; Perez-Reyes et al., 1998; Klugbauer et al., 1999; Lee et al., 1999; Monteil et al., 2000). The T-type calcium channels may be expressed in the whole body, such as in nervous tissue, the heart, the kidney, smooth muscles, and endocrine organs. The T-type calcium channels have been found to have functions of regulating burst-firing of nervous cells (Huguenard, J. R. et al., Annu. Rev. Physiol. 1996, 58, 329-348), heart pacemaker activity (Zhou, Z. et al., J. Mol. Cell. Cardiol. 1994, 26, 1211-1219), secretion of the hormone aldosterone (Rossier, M. E et al., Endocrinology 1996, 137, 4817-4826), and fertilization (Amoult, C. et al., Proc. Natl. Acad. Sci. 1996, 93, 13004-13009). Recently, it has been revealed that the T-type calcium channels are also associated with pain signaling (Ikeda, H. et al., Science, 2003, 299, 1237-1240).
A relationship between the expression of the T-type calcium channel and various diseases has been found. The expression of the T-type calcium channel in the brain has been found to be associated with nociception and repetitive low threshold firing. Particularly, a recent study has reported a direct relationship between the expression of the T-type calcium channel and pain using a knock-out mouse wherein the T-type calcium channel was deleted (Bourinet E. et al., EMBO, 2005, 24, 315-324; Shin, H. S. et al., Science, 2003, 302, 117-119). In addition, the T-type calcium channel is associated with epilepsy. Absence seizure, which is a type of epilepsy, is caused by over-activation of the T-type calcium channel in the brain (Tsakiridou E. et al., J. Neurosci. 1995, 15, 3110-3117). Ethosuccimide is an inhibitor against the T-type calcium channel, and has been used in treatment of absence seizure. The T-type calcium channel is commonly expressed in the heart and smooth muscles, and thus the inhibitors thereof can also be useful in treatment of hypertension, angina pectoris, and arrhythmia. Recently, it has been found that the T-type calcium channel is associated with the invasion and metastasis of cancer cells, and thus inhibitors thereof may be useful as anticancer drugs (Petty, H. R. et al., US 20060003020A1; McCalmont, W. F. et al, Bioorg. Med. Chem. Lett. 2004, 14, 3691-3695).
The exemplary inhibitor against the T-type calcium channel is miberfradil (Posicor®), developed by Roche. Mibefradil, which is a non-dihydropyridine calcium channel inhibitor, obtained FDA approval as a treatment drug against hypertension and angina pectoris in 1997. However, Mibefradil has been voluntarily removed since 1999 because of its side effect caused by drug-drug interaction by CYP 3A4 enzyme inhibition.
Therefore, efficient T-type calcium channel inhibitors have not yet been developed. In view of the effects of the T-type calcium channel on nerves, pain, epilepsy, hypertension, angina pectoris, heart muscle diseases, blood vessels, cancer metastasis, and the like, it has been required to develop efficient T-type calcium channel inhibitors that are capable of preventing and treating various T-type calcium channel associated diseases by inhibiting the over-expression and over-activation of the T-type calcium channel.
USPTO Backgrounds
USPTO Backgrounds