Piperazine derivatives and use as cysteine inhibitors

Details Piperazine derivatives and use as cysteine inhibitors Piperazine derivatives and use as cysteine inhibitors

1998-01-07

1999-08-10

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544372, 544374, A61K 31495, C07D40506, C07D40514

Patent

active

059359595

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a cysteine protease inhibitor composition comprising a piperazine derivative or a salt thereof as an active ingredient.


BACKGROUND TECHNOLOGY

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, 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 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 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.


DISCLOSURE OF THE INVENTION

The inventors of the present invention did much research to develop a drug substance which would show high cysteine protease-inhibitory activity and be highly membrane-permeable and comparatively stable in the in vivo environment. Consequently they discovered that a piperazine derivative of the following general formula (I) has potent cysteine protease-inhibitory activity and have perfected the present invention.
The present invention, therefore, is directed to a compound of the following formula (I) inclusive of its salt. ##STR3## carboxy which may be substituted; R.sup.2 represents hydrogen or lower alkyl and may be linked to either R.sup.3 or R.sup.4 to form a ring; R.sup.3 and R.sup.4 may be the same or different and each represents hydrogen, lower alkyl which may be substituted or a sulfide group which may be substituted; R.sup.3 and R.sup.4 may conjoinedly form a ring; R.sup.5 represents a substituted phenyl group of formula (II) ##STR4## (wherein R.sup.6 represents halogen or alkoxy) or a substituted sulfonyl group of formula (III) alkyl or amino which may be substituted); n is 0 or 1!.
The present invention is further directed to a pharmaceutical composition comprising the above compound and more particularly to a cysteine protease inhibitor composition comprising said compound.
Referring to the above general formula (I), the optionally esterified carboxy represented by R.sup.1 includes but is not limited to carboxy and alkoxycarboxy. The alkoxy moiety of said alkoxycarboxy may for example be C.sub.1-6 alkoxy and preferably C.sub.1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Particularly preferre

REFERENCES:
patent: 4507297 (1985-03-01), Masaki et al.
patent: 5556853 (1996-09-01), Tsubotani et al.
Abstract for JP63/275575 (Nov. 14, 1988), Mazaki.
Abstract for JP63/275576 (Nov. 14, 1988), Mazaki.

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