Substituted amides, their production and their use

Details Substituted amides, their production and their use Substituted amides, their production and their use

2000-10-03

2002-09-10

Shah, Mukund I. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S334000, C546S154000, C514S357000, C514S312000, C514S561000, C514S562000, C544S249000, C562S442000, C562S427000

Reexamination Certificate

active

06448254

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 B and L.
Calpains are intracellular, proteolytic enzymes from the so-called cysteine proteases group and are found in many cells. Calpains are activated by an increased calcium concentration, a differentiation 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). Still further calpain isoenzymes are postulated today (K. Suzuki et al.,
Biol. Chem
. Hoppe-Seyler, 1995, 376(9), 523-9).
It is suspected that calpains play an important part in various physiological processes. These include cleavage of regulatory proteins such as protein kinase C, cytoskeletal proteins such as MAP 2 and spectrin, muscle proteins, protein breakdown in rheumatoid arthritis, proteins in the activation of platelets, neuropeptide metabolism, proteins in mitosis and others which are listed in M. J. Barrett et al.,
Life Sci
. 1991, 48, 1659-69 and K. K. Wang et al.,
Trends in Pharmacol. Sci
., 1994, 15, 412-9.
Increased calpain levels have been measured in various pathophysiological processes, for example ischemias of the heart (e.g. cardiac infarct), of the kidney or of the central nervous system (e.g. “stroke”), inflammations, muscular dystrophy, cataracts of the eyes, injuries to the central nervous system (e.g. trauma), Alzheimer's disease etc. (see K. K. Wang, above). A relationship of these diseases with increased and lasting intracellular calcium levels is suspected. As a result, calcium-dependent processes are overactivated and are no longer subject to physiological regulation. Accordingly, overactivation of calpains can also initiate pathophysiological processes.
It was therefore postulated that inhibitors of the calpain enzymes can be useful for the treatment of these diseases. Various investigations confirm this. 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 shown a neuroprotective action of calpain inhibitors in acute neurodegenerative disorders or ischemias, such as occur after cerebral stroke. Likewise, after experimental brain traumata, calpain inhibitors improved recovery from the memory power deficits and neuromotor disorders which 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 a protective action of calpain inhibitors on kidneys damaged by hypoxia. Yoshida, Ken Ischi et al.,
Jap. Circ. J
. 1995, 59(1), 40-8, were able to show favorable effects of calpain inhibitors after cardiac damage which was produced by ischemia or reperfusion. Since calpain inhibitors inhibit the release of the &bgr;-AP4 protein, potential use as a therapeutic for Alzheimer's disease was proposed (J. Higaki et al.,
Neuron
, 1995, 14, 651-59). The release of interleukin-1&agr; is also inhibited by calpain inhibitors (N. Watanabe et al.,
Cytokine
1994, 6(6), 597-601). It was furthermore found that calpain inhibitors show cytotoxic effects on tumor cells (E. Shiba et al., 20
th Meeting Int. Ass. Breast Cancer Res., Sendai Jp
, Sep. 25-28 1994
, Int. J. Oncol
. 5 (Suppl.), 1994, 381).
Further 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. These are mainly, however, either irreversible or peptide inhibitors. As a rule, irreversible inhibitors are alkylating substances and have the disadvantage that they react nonselectively in the body or are unstable. Thus these inhibitors often show undesirable side effects, such as toxicity, and are accordingly restricted in their use or unutilizable. Among the irreversible inhibitors can be included, for example, the epoxides E 64 (E. B. McGowan et al.,
Biochem. Biophys. Res. Commun
. 1989, 158, 432-5), &agr;-haloketones (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,
Trends in Biol. Sci
. 1991, 16, 150-3). Under physiological conditions, peptide aldehydes have the disadvantage that they are often unstable on account of the great reactivity, can be rapidly metabolized and are prone to nonspecific reactions which can be the cause of toxic effects (J. A. Fehrentz and B. Castro,
Synthesis
1983, 676-78.
In JP 08183771 (CA 1996, 605307) and in EP 520336, aldehydes which are derived from 4-piperidinoylamides and 1-carbonylpiperidino-4-ylamides have been described as calpain inhibitors. However, the aldehydes claimed here, which are derived from heteroaromatically substituted amides of the general structure I, have previously been described. Other aldehyde derivatives have been described in Chatterjee et al. Bioorganic & Medicinal Chemistry Letters, 1997, 7, 287-290, Chatterjee et al. Bioorganic & Medicinal Chemistry Letters 1996, 6, 1619-1622, WO 97/10231 and WO 97/21690.
Peptide ketone derivatives are also inhibitors of cysteine proteases, in particular calpains. Thus, for example, in the case of serine proteases ketone derivatives are known as inhibitors, the keto group being activated by an electron-withdrawing group such as CF3 [sic]. In the case of cysteine proteases, derivatives with ketones activated by CF3 [sic] or similar groups are not very active or inactive (M. R. Angelastro et al.,
J. Med. Chem
. 1990, 33, 11-13). Surprisingly, in the case of calpain hitherto only ketone derivatives, in which, on the one hand, leaving groups in the &agr;-position cause an irreversible inhibition and, on the other hand, a carboxylic acid derivative activates the keto group, were found to be effective inhibitors (see M. R. Angelastro et al., see above; WO 92/11850; WO 92,12140; WO 94/00095 and WO 95/00535). However, of these ketoamides and ketoesters, virtually only peptide derivatives have been described as 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 above, M. R. Angelastro et al.). Only in Chatterjee et al. (see above) has a xanthene derivative of a ketobenzamide been described as a calpain inhibitor.
Ketobenzamides are already known in the literature. Thus the keto ester PhCO—Abu—COOCH
2
CH
3
was described in WO 91/09801, WO 94/00095 and 92/11850. The analogous phenyl derivative Ph—CONH—CH(CH
2
Ph)—CO—COCOOCH
3
was found in M. R. Angelastro et al.,
J. Med. Chem
. 1990, 33, 11-13 to be, however, only a weak calpain inhibitor. This derivative is also described in J. P. Burkhardt,
Tetrahedron Lett
., 1988, 3433-36. The significance of the substituted benzamides, however, has never been investigated until now.
In a number of therapies, such as stroke, the active compounds are administered intravenously as an infusion solution. For this purpose, it is necessary to have at one's disposal substances, in this case calpain inhibitors, which have sufficient water-solubility so that an infusion solution can be prepared. Many of the calpain inhibitors described, however, have the disadvantage that they only show a small or no water-solubility and are thus not suitable for intravenous administration. Active compounds of this type can only be administered using auxiliaries which are intended to impart water-solubility (cf. R. T. Bartus et al.
J. Cereb. Blood Flow Metab
. 1994, 14, 537-544). These auxiliaries, for example polyethylene glycol, frequently, however, have side effects or are even intolerable. A nonpeptide calpain inhibitor which is accordingly water-soluble

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