Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-03
2002-08-20
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S218000, C514S237800, C514S247000, C514S249000, C514S255030, C514S259500, C514S256000, C514S267000, C514S306000, C514S311000, C514S331000, C514S357000, C514S385000, C514S394000, C514S400000, C514S411000, C514S417000, C514S428000, C514S433000, C514S438000, C514S602000, C514S604000, C514S607000, C540S575000, C540S611000, C544S162000, C544S224000, C544S249000, C544S283000, C544S285000, C544S335000, C544S353000, C546S175000, C546S229000, C546S337000, C548S309700, C548S338100, C548S435000, C548S473000, C548S
Reexamination Certificate
active
06436925
ABSTRACT:
The present invention relates to novel benzamides 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, 367(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: ischemia 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. 20
th Meeting Int. Ass. Breast Cancer Res., Sendai Jp
, Sep. 25 to 28, 1994
Intl. 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 mainly peptide inhibitors. Many known reversible inhibitors of cysteine proteases such as calpain are, however, peptide aldehydes, in particular dipeptide and tripepide [sic] 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, owing to their great reactivity, that 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).
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). 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, many of these inhibitors are derived from peptides (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.).
Ketone derivatives which have a hetero group in the &agr; position have also been described as calpain inhibitors. Thus, sulfur derivatives (see EP 603873) and oxygen derivatives (see WO 95/15749 and R. E. Dolle et al.,
J. Med. Chem
. 1995, 38, 220-222) in which these hetero atoms are in the position &agr; to the ketone are known. Ketones which have an amino or amido group in the a position are likewise known, but usually in structures derived from peptides. Thus, EP 603873 has mentioned &agr;-amino radicals carrying a heterocycle. &agr;-Amides have likewise been described several times: D. L. Flynn et al.
J. Am. Chem. Soc
. 1997, 119, 4874-4881; S. Natarajan et al.,
J. Enzym. Inhib
. 1988, 2, 91-97; J. D. Godfrey et al.,
J. Org. Chem
. 1986, 51, 3073-3075; GB 2170200; EP 159156; EP 132304; U.S. Pat. No. 4,470,973 and JP 59033260. Most of the derivatives described therein are substituted on the amide residue by other amino acid derivatives. However, the amide
has likewise been described by D. L. Flynn et al. (see above). On the other hand, no derivatives in which the benzamide group has a substituent are mentioned. In addition, most of the compounds have been postulated as inhibitors of angiotensin converting enzyme.
An analogous sulfonamide but once again without substitution on the benzamide fragment has been described in R. F. Meyer et al.,
J. Med. Chem
. 1982, 25, 996-996 [sic], also as inhibitor of angiotensin converting enzyme. JP 06035142 (CA 121, 267626) has described benzamide derivatives analogous to the general structure I as photographic material, although heterocycles such as hydantoins or other groups sensitive to oxidation reactions stand in R
1
.
The novel compounds of the general formula I in which the substitutions on the benzamide and in the position &agr; to the keto group play important parts, with an amido or sulfonamido group being in the a position, have not previously been described and are accordingly novel.
In a number of therapies, such as [lacuna] 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 effe
Knopp Monika
Lubisch Wilfried
Möller Achim
Treiber Hans-Jörg
Abbott Laboratories
Keil & Weinkauf
McKenzie Thomas C
Shah Mukund J.
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