Benzamidoaldehydes and their use as cysteine protease...

Details Benzamidoaldehydes and their use as cysteine protease... Benzamidoaldehydes and their use as cysteine protease...

1999-05-26

2001-06-26

Huang, Evelyn Mei (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S312000, C514S345000, C514S347000, C514S355000, C514S357000, C514S617000, C514S618000, C514S619000, C514S620000, C514S621000, C514S622000, C546S153000, C546S157000, C546S172000, C546S293000, C546S314000, C546S316000, C546S337000, C564S161000, C564S162000, C564S164000, C564S166000, C564S168000, C564S169000, C564S180000, C564S181000

Reexamination Certificate

active

06251917

ABSTRACT:

The present invention relates to novel benzamidoaldehydes and to their application for controlling disorders.
Calpains are intracellular proteolytic enzymes of the group of the cysteine proteases and are found in many cells. Calpains are activated by elevated calcium concentrations, a distinction being made between calpain I or micro-calpain, which is activated by micro-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. 22(8) 1990, 811-22). Further calpain isoenzymes are now being postulated (K. Suzuki et al., Biol.Chem. Hoppe-Seyler, 376(9) (1995), 523-9).
Calpains are thought to play an important role in various physiological processes. These include: the cleavage of regulatory proteins—such as protein kinase C, cytoskeletal proteins (such as MAP 2 and spectrin), muscular proteins, proteins involved in the activation of platelets, proteins involved in mitosis and others which are listed in M. J. Barrett et al., Life Sci. 48 (1991), 1659-69 and K. K. Wang et al., Trends in Pharmacol.Sci., 15 (1994), 412-9; protein breakdown in rheumatoid arthritis and neuropeptide metabolism.
Elevated calpain levels were detected in various pathophysiological processes, for example, ischemia of the heart (for example myocardial infarction), the kidney or the central nervous system (for example stroke), inflammations, muscular dystrophies, cataracts of the eyes, injuries of the central nervous system (for example trauma) and Alzheimer's disease (see K. K. Wang, above). It is therefore assumed that these disorders are linked to increased intracellular calcium levels. Owing to this, calcium-dependent processes are overactivated and no longer subject to physiological regulation. Accordingly, an overactivation of calpains can also cause pathophysiological processes.
It has therefore been postulated that inhibitors of calpain enzymes may be useful for the treatment of these disorders. This has been confirmed by various studies. Thus, Seung-Chyul Hong et al., Stroke 25 (3) (1994), 663-9 and R. T. Bartus et al., Neurological Res. 17 (1995), 249-58, demonstrated a neuroprotective action of calpain inhibitors in acute neurodegenerative disorders or ischemia, such as occur after a stroke. After experimental brain trauma, calpain inhibitors improved the deficits of memory performance and the neuromotoric disorders that occurred (K. E. Saatman et al. Proc.Natl.Acad.Sci. USA, 93, (1996), 3428-3433). C. L. Edelstein et al., Proc.Natl.Acad.Sci. USA, 92 (1995), 7662-6, observed a protective activity of calpain inhibitors in kidneys damaged by hypoxia. Yoshida, Ken Ischi et al., Jap.Circ.J. 59(1) (1995), 40-8, were able to demonstrate favorable effects of calpain inhibitors after cardial damage brought about by ischemia or reperfusion. Since calpain inhibitors inhibit the release of the &bgr;-AP4 protein, a potential application as therapeutic agent for Alzheimer's disease has been suggested (J. Higaki et al., Neuron, 14 (1995), 651-59). The release of interleukin-1&agr; is also inhibited by calpain inhibitors (N. Watanabe et al., Cytokine 6(6) (1994), 597-601). It has furthermore been demonstrated that calpain inhibitors exhibit cytotoxic effects in 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 applications of calpain inhibitors are listed in K. K. Wang, Trends in Pharmacol.Sci., 15 (1994), 412-8.
Calpain inhibitors have already been described in the literature. However, they are predominantly either irreversible or peptidic inhibitors. Irreversible inhibitors are usually alkylating substances, which have the disadvantage that they react nonselectively in the organism or that they are instable. For this reason, these inhibitors often exhibit undesirable side-effects, such as toxicity, and their applications are therefore limited, or they are not useful. The irreversible inhibitors include, for example, the epoxides E 64 (E. B. McGowan et al., Biochem.Biophys.Res.Commun. 158 (1989), 432-5), &agr;-haloketones (H. Angliker et al., J.Med.Chem. (1992), 216-20) and disulfides (R. Matsueda et al., Chem.Lett. (1990), 191-194).
Many known reversible inhibitors of cysteine proteases, such as calpain, are peptidic aldehydes or ketones, in particular dipeptidic and tripeptidic aldehydes, such as, for example, Z-Val-Phe-H (MDL 28170) (S. Mehdi, Trends in Biol.Sci. 16 (1991), 150-3) and the compounds of EP 520336. Under physiological conditions, peptidic aldehydes for example often have the disadvantages that they are unstable owing to the reactivity present (J. A. Fehrentz and B. Castro, Synthesis, 19983 [sic], 676-678), that they can be metabolized quickly, that they have low water-solubility (important for intravenous application) or that they are slow to cross cell membranes, such as the blood-brain barrier and cellular membranes of neurons (calpain is an intracellular enzyme and any inhibitor has to penetrate into the cells). Thus, the best known peptidic inhibitors MDL 28170, AK 275 and AK 295 (Seung-Chuyl Hong et al., Stroke 25(3) (1994), 663-669; R. T. Bartus et al., J.Cerebral Blood Flow and Metabolism, 14 (1994), 537-544) have been studied pharmacologically in animals, but effects were only observed when the substances were applied in a manner which is unconventional for treatment, for example intracerebroventricularly or intra-arterially. The use of the known calpain-inhibiting peptidic aldehydes or ketones in the treatment of disorders is therefore limited or not advantageous.
Furthermore, efforts are being made to develop reversible non-peptidic calpain inhibitors. Thus, JP 8183759, JP 8183769, JP 8183771 and EP 520336 describe aldehydes derived from dipeptides where saturated carbocyclic rings, for example cyclohexanes, or saturated heterocyclic rings, for example piperidines, were incorporated into these peptidic inhibitors replacing an amino acid, affording novel calpain inhibitors.
Furthermore, compounds have also been described which are derived from the structure
in particular compounds where aryl is a phenyl ring which may carry simple substituents such as alkyl radicals (WO 95/09838; WO 93/14082; WO/12140; Synthesis 181 (1995); EP 363284; J 59206-344 and DT 2050679). However, as shown in Synthesis 181 (1995), compounds where aryl=phenyl are only weak inhibitors of the enzyme calpain. It is not known whether substituents on this phenyl ring influence the inhibitory activity of the compounds.
It is an object of the present invention to provide non-peptidic benzamidoaldehydes having an improved activity.
We have found that this object is achieved by benzamidoaldehydes of the formula I
and their tautomeric and isomeric forms and, if appropriate, their physiologically acceptable salts, where:
R
1
is phenyl, naphthalene, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, pyridine, pyrimidine, pyrazine, pyridazine, quinazoline, quinoxaline, thiophene, benzothiophene, benzofuran, furan or indole, where the aromatic and heteroaromatic rings may be substituted by up to three radicals R
4
,
R
2
is hydrogen, chlorine, bromine, fluorine, phenyl with or without substitution by a C
1
-C
4
-hydrocarbon radical, —NHCO-C
1
-C
4
-alkyl, —NHCOPh, —NHCO-naphthyl, —NHSO
2
-C
1-4
-alkyl, CONH
2
, COOH, —COO-C
1-4
-alkyl, —O-C
1-4
-alkyl, —CO—NH-C
1-4
-alkyl, NO
2
or NH
2
,
R
3
is a C
1
-C
6
-hydrocarbon radical, which may also carry a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indolyl, phenyl, pyridine or naphthyl ring, it being possible for the rings in turn to be substituted by one or two radicals R
4
, or is an —SCH
3
radical,
R
4
is C
1
-C
4
-alkyl, —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, —(CH
2
)
n
—NR
5
R
6
(R
5
and R
6
are identical or different and are each hydrogen, C
1-4
-alkyl or together are a ring), —SO
2
-C

Affiliated with

Also associated with

Rating

Benzamidoaldehydes and their use as cysteine protease... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Benzamidoaldehydes and their use as cysteine protease..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzamidoaldehydes and their use as cysteine protease... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2542723