Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-15
2002-11-19
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S144000, C546S167000, C514S314000, C514S311000
Reexamination Certificate
active
06482832
ABSTRACT:
The present invention relates to novel amides which are inhibitors of enzymes, in particular cysteine proteases, such as calpain (=calcium-dependent cysteine proteases) and its isoenzymes and cathepsins, for example cathepsins B and L. Calpains are intracellular, proteolytic enzymes from the cysteine protease group and are found in many cells. Calpains are activated by an elevated calcium concentration, with a distinction being made between calpain I or &mgr; calpain, which is activated by &mgr; molar concentrations of calcium ions, and calpain II or m calpain, which is activated by m molar concentrations of calcium ions (P. Johnson, Int. J. Biochem. 1990, 22(8), 811-22). Further calpain isoenzymes are nowadays being postulated (K. Suzuki et al., Biol. Chem. Hoppe-Seyler, 1995, 376(9),523-9).
Calpains are presumed to play an important role in a variety of physiological processes. These include the cleavage of regulatory proteins such as protein kinase C, cytoskeletal proteins such as MAP 2 and spectrin, muscle proteins, protein degradation in rheumatoid arthritis, proteins involved in the activation of platelets, neuropeptide metabolism, proteins in mitosis and other proteins which are listed in M. J. Barrett et al., Life Sci. 1991, 48, 1659-69 and K. K. Wang et al. and Trends in Pharmacol. Sci., 1994, 15, 412-9.
Elevated levels of calpain have been measured in a variety of pathophysiological processes, for example: ischemias of the heart (e.g. cardiac infarction), of the kidney or of the central nervous system (e.g. stroke), inflammations, muscular dystrophies, cataracts of the eyes, injuries to the central nervous system (e.g. trauma), Alzheimer's disease, etc. (see K. K. Wang, above). It is assumed that there is a connection between these diseases and persistently elevated intracellular calcium levels. These levels result in calcium-dependent processes becoming hyperactivated and no longer being subject to physiological control. Correspondingly, hyperactivation of calpains can also induce other pathophysiological processes.
It has therefore been postulated that inhibitors of the calpain enzymes could be useful for treating these diseases. This is confirmed by a variety of investigations. Thus, Seung-Chyul Hong et al., Stroke 1994, 25(3), 663-9 and R. T. Bartus et al., Neurological Res. 1995, 17, 249-58 have demonstrated that calpain inhibitors have a neuroprotective effect in acute neurodegenerative disturbances or ischemias which occur after a stroke. In the same way, following experimental brain traumas, calpain inhibitors improved recovery of the memory performance deficits and neuromotor disturbances which had occurred (K. E. Saatman et al. Proc. Natl. Acad. Sci. USA, 1996, 93,3428-3433). C. L. Edelstein et al., Proc. Natl. Acad. Sci. USA, 1995, 92, 7662-6, found calpain inhibitors to have a protective effect on kidneys damaged by hypoxia. Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59(1), 40-8, demonstrated calpain inhibitors to have favorable effects following cardiac damage produced by ischemia or reperfusion. Since calpain inhibitors inhibit the release of &bgr;-AP4 protein, it has been proposed that they could have a potential use as therapeutic agents in Alzheimer's disease (J. Higaki et al., Neuron, 1995, 14, 651-59). Calpain inhibitors also inhibit the release of interleukin-la (N. Watanabe et al., Cytokine 1994, 6(6), 597-601). Furthermore, it has been found that calpain inhibitors have cytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int. Ass. Breast Cancer Res., Sendai Jp, 1994, 25.-28. Sept., Int. J. Oncol. 5(Suppl.), 1994, 381).
Other possible uses of calpain inhibitors are listed in K. K. Wang, Trends in Pharmacol. Sci., 1994, 15, 412-8.
Calpain inhibitors have already been described in the literature. However, those which have been described are predominantly either irreversible inhibitors or peptide inhibitors. As a rule, irreversible inhibitors are alkylating substances and suffer from the disadvantage that they either react nonselectively in the organism or are unstable. Thus, these inhibitors often exhibit undesirable side effects, such as toxicity, and, as a consequence, are of restricted use or cannot be used at all. Examples of irreversible inhibitors which can be mentioned are the E 64 epoxides (E. B. McGowan et al., Biochem. Biophys. Res. Commun. 1989, 158, 432-5), &agr;-halogenoketones (H. Angliker et al., J. Med. Chem. 1992, 35, 216-20) or disulfides (R. Matsueda et al., Chem. Lett. 1990, 191-194).
Many known reversible inhibitors of cysteine proteases such as calpain are peptide aldehydes, in particular dipeptide and tripeptide aldehydes such as, for example, Z-Val-Phe-H (MDL 28170) (S. Mehdi, Tends in Biol. Sci. 1991, 16, 150-3). Under physiological conditions, peptide aldehydes suffer from the disadvantage that, because of their high degree of reactivity, they are frequently unstable, can be metabolized rapidly and have a tendency to participate in nonspecific reactions which can be the cause of toxic effects (J. A. Fehrentz and B. Castro, Synthesis 1983, 676-78.
JP 08183771 (CA 1996, 605307) and EP 520336 describe aldehydes which are derived from piperidin-4-ylcarboxamides and 1-carbonylpiperidin-4-ylcarboxamides and which are calpain inhibitors. However, the aldehydes which are claimed in this present document, and which are derived from heteroaromatically substituted amides of the general structure I, have not been described previously.
Peptide ketone derivatives are also inhibitors of cysteine proteases, in particular calpains. For example, ketone derivatives in which the keto group is activated by an electrophilic group such as CF
3
are known to be inhibitors of serine proteases. Derivatives which contain ketones which are activated by CF
3
or similar groups are not particularly active, or are not active at all, in the case of cysteine proteases (M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13). Surprisingly, the only ketone derivatives which have so far been found to be effective inhibitors of calpain are those in which, on the one hand, leaving groups in the a position cause an irreversible inhibition and, on the other hand, a carboxylic acid derivative activates the keto group (see M. R. Angelastro et al., see above; WO 92/11850; WO 92/12140; WO 94/00095 and WO 95/00535). However, only peptide derivatives of these ketoamides and ketoesters have so far been reported to be effective (Zhaozhao Li et al., J. Med. Chem. 1993, 36, 3472-80; S. L. Harbenson et al., J. Med. Chem. 1994, 37, 2918-29 and see M. R. Angelastro et al., see above).
Ketobenzamides have already been disclosed in the literature. Thus, the ketoester PhCO—Abu—COOCH
2
CH
3
has been described in WO 91/09801, WO 94/00095 and WO 92/11850. However, in M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13, the analogous phenyl derivative Ph—CONH—CH(CH
2
Ph)—CO—COCOOCH
3
was found to be only a weak calpain inhibitor. This derivative is also described in J. P. Burkhardt, Tetrahedron Lett., 1988, 3433-36. However, the importance of the substituted benzamides has thus far never been investigated.
In a number of therapies such as stroke, the active compounds are administered intravenously, for example as an infusion solution. For this, it is necessary to have available substances, in this case calpain inhibitors, which are sufficiently water-soluble to enable an infusion solution to be prepared. However, many of the calpain inhibitors which have been described suffer from the disadvantage that they are only sparingly soluble or insoluble in water and consequently not suitable for intravenous administration. Active compounds of this nature can only be administered using auxiliary substances whose purpose is to mediate solubility in water (cf. R. T. Bartus et al.
J. Cereb. Blood Flow Metab
. 1994, 14, 537-544). However, these auxiliary substances, such as polyethylene glycol, frequently have attendant effects or cannot in fact be tolerated. It would consequently be a great advantage to have available a nonpeptide calpain inhibitor which
Knopp Monika
Lubisch Wilfried
Möller Achim
Treiber Hans-Jörg
Abbott Laboratories
Keil & Weinkauf
Liu Hong
Shah Mukund J.
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