Ketobenzamides as calpain inhibitors

Details Ketobenzamides as calpain inhibitors Ketobenzamides as calpain inhibitors

1999-06-08

2000-08-15

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514249, 514311, 514319, 514399, 514506, 546162, 546169, 546195, 544355, 5483381, 560 24, 560 33, A61K 31535, A61K 31495, A61K 3121, C07D24136, C07D23354

Patent

active

061037206

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP97/06655 Nov. 28, 1997.
The present invention relates to novel ketobenzamides, to their preparation and to their use in controlling diseases.
Calpains are intracellular, proteolytic enzymes from the cysteine protease group and are found in many cells. Calpains are activated by elevated calcium concentration, with a distinction being made between calpain I or .mu.-calpain, which is activated by .mu.-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 currently being postulated (K. Suzuki et al., Biol. Chem. Hoppe-Seyler, 1995, 376(9),523-9).
It is assumed that calpains play an important role in various physiological processes. These processes include the cleavage of regulatory proteins such as protein kinase C, cytoskeletal proteins such as MAP 2 and spectrin, and muscle proteins, protein degradation in rheumatoid arthritis, proteins in the activation of platelets, neuropeptide metabolism, proteins in mitosis, and additional examples 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.
Elevated calpain levels can be measured in various pathophysiological processes, for example: ischemias of the heart (eg. myocardial infarction), the kidney or the central nervous system (eg. stroke), inflammations, muscular dystrophies, cataracts of the eyes, injuries to the central nervous system (eg. 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. This results in calcium-dependent processes becoming hyperactivated and no longer being subject to physiological control. A corresponding hyperactivation of calpains can also trigger pathophysiological processes.
For this reason, it was postulated that inhibitors of the calpain enzymes could be of use for treating these diseases. This postulate 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 such as occur after cerebral stroke. Following experimental brain traumas, calpain inhibitors improved recovery from the memory performance deficits and neuromotor disturbances 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 that calpain inhibitors have a protective effect on hypoxia-damaged kidneys. Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59(1), 40-8 pointed out that calpain inhibitors had favorable effects following cardiac damage which was produced by ischemia or reperfusion. Since calpain inhibitors inhibit the release of the .beta.-AP4 protein, it was suggested that they had a potential use as therapeutic agents in Alzheimer's disease (J. Higaki et al., Neuron, 1995, 14, 651-59). The release of interleukin-1.alpha. is also inhibited by calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6(6), 597-601). It has furthermore been found that calpain inhibitors have cytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int. Ass. Breast Cancer Res., Sendai J p, 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. However, these are predominantly either irreversible inhibitors or peptide inhibitors. As a rule, irreversible inhibitors are alkylating substances and suffer from the disadvantage that they react unselectively in the organism or are unstable. Thus, these inhibitors often exhibit undesirable side-effects, such as toxicity, and as a result are

REFERENCES:
patent: 5162500 (1992-11-01), Takeuchi et al.
patent: 5496927 (1996-03-01), Kolb et al.
Sebti et al, "Inhibitors of protein isoprenyl transferases", CA130:25338, 1998.
Int.J. Bio., vol. 23, No. 9, 819-821, 1991.
Bio. Chem. vol. 3876, No. 1, Jan. 1995, Suzuki et al., 523-529.
Life Sci., vol. 48, 1659-1669, Barrett et al, 1995.
Tips, Nov. 1994, vol. 14, Wang et al., 412-419.
Stroke, vol. 24, No. 3, Mar. 1994, Hong et al., 662-668.
Neu. Res., 1995, vol. 17, Aug., Bartus et al., 249-258.
Proc. Natl. Acad. Sci, vol. 93, 3428-3433, Apr. 1996, Saatman et al.
Tet. letts. vol. 29, No. 28, Burkhart et al., 3433-36, 1998.
J. Med Chem, 1993,36, 3472-80, Girish et al.
J. Med Chem., 1994, 37, 2918-29, Harbeson et al.
Synthesis, 1983, No. 8, Aug., 676-678.
J. Med. Chem. 1990, 33, 11-13.
Proc. Natl. Acad. Sci, vol. 92, 7662-7666, Aug. 1995, Edelstein et al.
J. Cir. J., vol. 59, Jan. 1995; Yoshida et al., 40-48.
Neuron, vol. 14, 651-659, Mar. 1995, Higaki et al.
Cytokine, vol. 6, No. 6, Nov. 1994, 597-601, Watanabe et al.
Int.J.Oncology 5: Supp., 1994, 381.
Bio. and Bio. Res. Com. vol. 158, No. 2, 1989, 432-435 McGowan et al.
J. Med. Chem, 1992, 35, 216-220, Angliker et al.
Chem. Letts., 191-194, 1990, Matsueda et al.
TIBS, vol. 16, 1991, 150-153.

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