Heterocyclically substituted amides used as calpain inhibitors

Details Heterocyclically substituted amides used as calpain inhibitors Heterocyclically substituted amides used as calpain inhibitors

2000-10-03

2003-05-13

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S211010, C514S247000, C514S253010, C540S484000, C540S524000, C544S358000, C544S360000, C546S001000, C546S268100, C546S329000, C546S339000

Reexamination Certificate

active

06562827

ABSTRACT:

The present invention relates to novel heterocyclically substituted 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. The enzyme calpain is 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). The existence of further calpain isoenzymes is 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: ischemia of the heart (e.g. cardiac 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). 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; was 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., 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 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 non-selectively 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) and the compounds from EP 520336.
Peptide ketone derivatives have also been disclosed as inhibitors of cysteine proteases and in particular calpain. However, only ketones, 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, hitherto 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.).
Until now, it has never been shown that nonpeptide ketones are also potent, reversible calpain inhibitors. The aim is thus to obtain nonpeptide inhibitors which are derived from carbonyl compounds and improve the general problems of peptides (metabolic stability, poor crossing of the cell membranes etc.).
Ketobenzamides are already known in the literature. Thus the ketoester 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 heterocyclically substituted amides, however, has never been investigated until now.
On the other hand, there are attempts to find reversible nonpeptide calpain inhibitors. Thus in JP 8183759, JP 8183769, JP 8183771 and EP 520336 aldehydes derived from dipeptides have already been described, saturated carbocyclic rings, for example cyclohexanes, or saturated heterocyclic rings, for example piperidines, being incorporated into these peptide inhibitors instead of an amino acid and novel aldehydes being obtained as calpain inhibitors.
In the present invention, substituted nonpeptide heterocyclically substituted amide derivatives are described. These compounds are new and surprisingly have the possibility of obtaining potent nonpeptide inhibitors of cysteine proteases, such as, for example, calpain, by incorporation of rigid structural fragments.
The present invention relates to heterocyclically substituted amides of the general formula I
and their tautomeric and isomeric forms, possible enantiomeric and diastereomeric forms, as well as possible physiologically tolerable salts, in which the variables have the following meanings:
A is piperazine, homopiperazine, piperidine or pyrrolidine, which can additionally carry a radical R
5
and
B is a phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring and
R
1
and R
2
independently of one another are hydrogen, C
1
-C
6
-alkyl, which is branched or unbranched, O—C
1
-C
6
-alkyl, which is branched or unbranched, OH, Cl, F, Br, I, CF
3
, NO
2
, NH
2
, CN, COOH, COO—C
1
-C
4
-alkyl, NHCO—C
1
-C
4
-alkyl, NHCO-phenyl, CONHR
9
, NHSO
2
—C
1
-C
4
-alkyl, NHSO
2
-phenyl, SO
2
—C
1
-C
4
-alkyl and SO
2
-phenyl and R
1
and R
2
can be a chain —CH═CH—CH═CH—, which can additionally carry one or two substituents R
6
, and
R
3
is C
1
-C
6
-alkyl, which is branched or unbranched and which can additionally carry an S—CH
3
radical, cyclohexyl, cyclopentyl, cycloheptyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, indolyl, thienyl or napht

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