Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-15
2002-04-30
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S235500, C514S314000, C514S318000, C514S319000, C514S324000, C544S129000, C546S176000, C546S194000, C546S202000, C546S205000, C546S209000, C546S226000, C546S227000
Reexamination Certificate
active
06380220
ABSTRACT:
The present invention relates to novel ketoesters and ketoamides which are inhibitors of enzymes, in particular cysteine proteases, such as calpain (=calcium-dependant cysteine protease and its isoenzymes and cathepsins, for example B and L.
Calpains are intracellular, proteolytic enzymes from the cysteine proteases group and are found in many cells. The enzyme calpain is activated by 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). Today, still further calpain isoenzymes are postulated (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 mentioned 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 were measured in various pathophysiological processes, for example: ischemias of the heart (eg. cardiac infarcts), of the kidney or the central nervous system (eg. stroke), inflammation, muscular dystrophy, cataracts of the eyes, injuries to the central nervous system (eg. trauma), Alzheimer's disease etc. (see K. K. Wang, above). A relationship of these diseases with increased and lasting intracellular calcium levels is presumed. As a result, calcium-dependent processes are overactivated and no longer subjected to physiological regulation. Accordingly, overactivation of calpains can also trigger pathophysiological processes.
It was therefore postulated that inhibitors of the calpain enzymes may 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, such as occur after stroke. Likewise, after experimental cerebral traumas, calpain inhibitors improved the recovery from the memory power deficits and neuromotor disorders occurring (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, a 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 likewise 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, 1994, 25.-28. Sept., Int. J. Oncol. 5(Suppl.), 1994, 381).
Further possible uses of calpain inhibitors are mentioned in K. K. Wang, Trends in Pharmacol. Sci., 1994, 15, 412-9.
Calpain inhibitors have already been described in the literature. Mainly, however, these are either irreversible or peptide inhibitors. As a rule, irreversible inhibitors are alkylating substances and have the disadvantage that they have an unselective reaction in the body or are unstable. Thus these inhibitors often show undesired side effects, such as toxicity, and are then restricted in their use or unutilizable. Among the irreversible inhibitors can be counted, 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. 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). The use of peptide aldehydes in the treatment of diseases is thus restricted or ineffective. It is thus surprising that only a few aldehydes can be employed as active compounds, namely especially when the aldehyde group is stabilized, for example by hemiacetal formation.
An advance is the discovery that certain peptide ketone derivatives are also inhibitors of cysteine proteases and, in particular, calpain. Thus in the case of serine proteases for example, ketone derivatives are known as inhibitors, the keto group being activated by an electron-withdrawing group such as CF
3
. In the case of cysteine proteases, derivatives with ketones activated by CF
3
or similar groups are less active or inactive (M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13). Surprisingly, in the case of calpain, until now only ketone derivatives in which on the one hand &agr;-position leaving groups cause an irreversible inhibition and on the other hand a carboxylic acid derivative activates the keto group, were found as active 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, only peptide derivatives have previously been described as active (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.).
It is an object of the present invention to make available nonpeptide inhibitors which are derived from the more stable ketones and which do not have the general problems of peptides, (metabolic stability, difficulty in getting through the cell membranes etc.).
The present invention relates to piperidineketocarboxylic acid derivatives of the formula I
and their tautomeric and isomeric forms, and possible physiologically tolerable salts, where the variables have the following meanings:
R
1
is —CO—R
4
, —SO
2
—R
4
, —CONH—R
4
, COOR
4
, —C(═N)—R
4
, —C(═O) —NHR
4
and —C(═S)—NHR
4
;
R
2
is —C
1
-C
6
-alkyl, which is branched or unbranched and can additionally carry a phenyl, pyridine or naphthyl ring which in turn can be substituted by at most two radicals R
5
, it being possible for R
5
to be C
1
-C
4
-alkyl which is branched or unbranched, —O—C
1
-C
4
-alkyl, 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, —NHCOPh, —NHSO
2
—C
1
-C
4
-alkyl, NHSO
2
—Ph, —SO
2
—C
1
-C
4
-alkyl and —SO
2
Ph;
R
3
is —OR
6
or —NHR
6
;
R
4
is —C
1
-C
6
-alkyl which is branched or unbranched, it also being possible for a chain of two or more C atoms to contain a double bond or triple bond and to be substituted by one or two rings such as phenyl, naphthalene, quinoxaline, quinoline, isoquinoline, pyridine, thiophene, benzothiophene, benzofuran, pyrimidine, thiazole, isothiazole, triazole, imidazole, cyclohexyl, cyclopentyl, fluorene, indole, benzimidazole, oxazole, isooxazole and furan, it being possible for each of the rings themselves additionally to carry at most two radicals R
5
;
R
6
is hydrogen, a phenyl ring which can additionally carry one or two radicals R
5
, C
1
-C
6
-alkyl which is branched or unbranched and can contain a double bond or a triple bond, and a rin
Delzer Jürgen
Lubisch Wilfried
Möller Achim
Abbott Laboratories
Chang Ceila
Keil & Weinkauf
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