Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-11
2004-06-22
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235200, C514S235800, C514S239500, C514S252120, C514S315000, C514S408000, C514S415000, C514S616000, C514S620000, C540S484000, C544S139000, C544S143000, C544S168000, C544S400000, C546S234000, C548S495000, C548S578000, C564S157000, C564S164000
Reexamination Certificate
active
06753327
ABSTRACT:
This application is a national phase application of PCT/EP 99/02633 filed Apr. 20, 1999 which claims the priority of German patent application No. 19818615.0 filed Apr. 20, 1998.
The present invention relates to novel amides which are inhibitors of enzymes, especially cysteine proteases such as calpain (=calcium dependant cysteine proteases) and its isoenzymes and cathepsins, for example B and L.
Calpains are intracellular proteolytic enzymes from the group of cysteine proteases and are found in many cells. Calpains are activated by an increase in the calcium concentration, 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 have now been postulated too (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 cleavages of regulatory proteins such as protein kinase C, cytoskeletal proteins such as MAP 2 and spectrin, muscle proteins, protein degradation 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.
Elevated calpain levels have been measured in various pathophysiological processes, for example: ischemias of the heart (e.g. myocardial infarct), 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 suspected that there is a connection between these disorders and elevated and persistent intracellular calcium levels. This results in overactivation of calcium-dependent processes, which are then no longer subject to physiological control. Accordingly, overactivation of calpains may also induce pathophysiological processes.
It has therefore been postulated that inhibitors of calpain enzymes may be useful for treating these disorders. Various investigations have confirmed 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 effect of calpain inhibitors in acute neurodegenerative disorders or ischemias like those occurring after stroke. Likewise, calpain inhibitors improved the recovery of the memory deficits and neuromotor disturbances occurring after experimental brain trauma (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 effect 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 beneficial effects of calpain inhibitors after cardiac damage produced by ischemia or reperfusion. Since the release of the &bgr;-AP4 protein is inhibited by calpain inhibitors, a potential therapeutic use for Alzheimer's disease has been proposed (J. Higaki et al., Neuron, 1995, 14, 651-59). The release of interleukin-1&agr; is likewise inhibited by calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6(6), 597-601). It has further been found that calpain inhibitors have cytotoxic effects on tumor cells (E. Shiba et al. 20th 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 detailed 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 or peptide inhibitors. Irreversible inhibitors are usually alkylating substances and have the disadvantage that they react nonselectively or are unstable in the body. Thus, these inhibitors often show unwanted side effects such as toxicity, and are accordingly of limited use or unusable. The irreversible inhibitors can be said to include, for example, the epoxides E 64 (E. B. McGowan et al., Biochem. Biophys. Res. Commun. 1989, 158, 432-5), &agr;-halo ketones (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, owing to the high reactivity, they are often unstable, may be rapidly metabolized and are prone to nonspecific reactions which may cause toxic effects (J. A. Fehrentz and B. Castro, Synthesis 1983, 676-78).
JP 08183771 (CA 1996, 605307) and EP 520336 have described aldehydes derived from 4-piperidinoylamides [sic] and 1-carbonyl-4-piperidinoylamides [sic] as calpain inhibitors. However, the aldehydes which are claimed herein and are derived from amides of the general structure I with heteroaromatic substituents have previously been described [sic]
Peptide ketone derivatives are likewise inhibitors of cysteine proteases, in particular calpains. Thus, for example, ketone derivatives where the keto group is activated by an electron-attracting group such as CF
3
are known to be inhibitors of serine proteases. In the case of cysteine proteases, derivatives with ketones activated by CF
3
or similar groups have little or no activity (M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13). Surprisingly, to date only ketone derivatives in which, on the one hand, leaving groups in the a position cause irreversible inhibition and, on the other hand, the keto group is activated by a carboxylic acid derivative have been found to be effective inhibitors of calpain (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 keto amides and keto esters have to date 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.).
Ketobenzamides have already been described in the literature. Thus, the keto ester PhCO—Abu—COOCH
2
CH
3
has been 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, however, found to be only a weak calpain inhibitor in M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13. This derivative is also described in J. P. Burkhardt, Tetrahedron Lett., 1988, 3433-36. The significance of the substituted benzamides has, however, never been investigated to date.
In a number of therapies, such as for stroke, the active ingredients are administered intravenously, for example as infusion solution. To do this it is necessary to have available substances, in this case calpain inhibitors, which have adequate solubility in water so that an infusion solution can be prepared. Many of the described calpain inhibitors have, however, the disadvantage that they have only low or no solubility in water and thus are unsuitable for intravenous administration. Active ingredients of this type can be administered only with ancillary substances intended to confer solubility in water (cf. R. T. Bartus et al. J. Cereb. Blood Flow Metab. 1994, 14, 537-544). These ancillary substances, for example polyethylene glycol, often have side effects, however, or are even incompatible. A non-peptide calpain inhibitor which is soluble in water without ancillary substances would thus be a great advantage. No such inhibitor has been described to date, and it would thus be novel.
Non-peptide aldehydes, keto carboxylic esters and keto amide derivatives were described in the present
Knopp Monika
Lubisch Wilfried
Möller Achim
Treiber Hans-Jörg
Abbott & GmbH & Co. KG
Raymond Richard L.
Wood Phillips Katz Clark & Mortimer
LandOfFree
Substituted amides, their preparation and use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted amides, their preparation and use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted amides, their preparation and use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3305390