Cysteine protease is a protease having a cysteine residue in the activity center of the enzyme molecule and includes such species as cathepsin B, H, and L and dipeptidyl peptidase, all of which are lysosomal enzyme fractions, and calpain which exists in the cytoplasm, among others. Though much remains to be explored about the physiological roles of these enzymes, a considerable amount of work has been done on their roles in recent years. For example, calpain is known to be a protease ubiquitous in life, which is activated by calcium ions and has the optimum pH in the neighborhood of neutral. As elucidated to this day, it takes part in degradation of the skeletal protein of cells, activation of inert cell precursors such as protein kinase C, and degradation of receptor proteins. It has also been shown that the abnormality of this enzyme activity is involved in many diseases, for example, refractory diseases such as cerebral apoplexy (stroke), subarachnoid hemorrhage, Alzheimer's disease, ischemic diseases, myodystrophy, cataract, platelet aggregation disorder, arthritis, and osteoporosis, among other diseases. Trends in Pharmacological Sciences, 15, 412, 1994!.
As inhibitors of such cysteine proteases, several peptide compounds inclusive of an epoxysuccinic acid peptide derivative (JP-B 1-54348, JP-A 55-153778, etc.), a peptidoaldehyde derivative (JP-B 45-17154, JP-B 46-22012, etc.), a peptidohalomethane derivative (JP-B 6-29229), and a peptidohalohydrazide derivative Eur. J. Med. Chem., 28, 297-311, 1993! have been reported. As enzymes having calpain-inhibitory activity among various kinds of cysteine proteases, several peptide compounds such as a peptide aldehyde derivative (JP-A 6-287167), a peptidodiazomethane derivative Biochem, J., 253, 751-758, 1988, J. Med. Chem., 35, 216-220, 1992!, a peptidodisulfide derivative Chem. Lett., 191-194, 1990!, etc. and several non-peptide compounds such as an isocoumarin derivative (WO 92/11850), KP-1241 (JP-A 6-41067), etc. have also been reported. Moreover, as inhibitors of cathepsin L and B, an aldehyde derivative (JP-A 7-101924) and an epoxysuccinic acid derivative (JP-A 8-104683, WO 95/32954) have been reported.
However, many of these known inhibitors are not fully satisfactory in transferability to the cell and/or in vivo stability, while others are not as effective as desired, with the result that there is not available a clinically useful inhibitor.
USPTO Backgrounds
USPTO Backgrounds