Heterocyclically substituted benzamides and their use

Details Heterocyclically substituted benzamides and their use Heterocyclically substituted benzamides and their use

2000-09-21

2002-08-20

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S418000, C514S257000, C514S267000, C548S452000, C548S465000, C548S473000, C548S477000, C544S249000, C544S309000

Reexamination Certificate

active

06436949

ABSTRACT:

The present invention relates to novel heterocyclically substituted benzamides and their use in the control of diseases.
Calpains are intracellular, proteolytic enzymes from the cysteine protease group and are found in many cells. Calpains are activated by an elevated concentration of calcium, with 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 mmolar concentrations of calcium ions (P. Johnson, Int.J.Biochem. 1990, 22(8), 811-22). Nowadays, the existence of other calpain isoenzymes is also postulated (K. Suzuki et al., Biol.Chem. Hoppe-Seyler, 1995, 376(9), 523-9).
Calpains are presumed to play an important role in various physiological processes including the cleavage of regulatory proteins such as protein kinase C, cytoskeletal proteins such as MAP 2 and spectrin, and muscle proteins, protein degradation in rheumatoid arthritis, proteins associated with 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 levels of calpain have been measured in various pathophysiological processes, for example: ischemias of the heart (eg. cardiac infarction), of the kidney or of the central nervous system (eg. stroke), inflammations, muscular dystrophies, cataracts of the eyes, injuries to the central nervous system (eg. trauma), Alzheimer's disease, etc. (see K. K. Wang, above). These diseases have a presumed association with elevated and persistent intracellular calcium levels, which cause calcium-dependent processes to be overactivated and no longer subject to physiological control. In a corresponding manner, overactivation of calpains can also trigger pathophysiological processes.
For this reason, it was postulated that inhibitors of the calpain enzymes might be of value for treating these diseases. This has been confirmed by a variety of investigations. For example, Seung-Chyul Hong et al., Stroke 1994, 25(3), 663-9 and R. T. Bartus et al., Neurological Res. 1995, 17, 249-58 have demonstrated that calpain inhibitors have a neuroprotective effect in acute neurodegenerative disturbances or ischemias, as occur following cerebral stroke. Calpain inhibitors improved recovery from the memory performance deficits and neuromotor disturbances which occurred following experimental brain traumas (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 that calpain inhibitors have a protective effect on hypoxia-damaged kidneys. Yoshida, Ken Ischi et al., Jap.Circ.J. 1995, 59(1), 40-8, were able to demonstrate that calpain inhibitors exerted beneficial effects following cardiac damage caused by ischemia or reperfusion. Since calpain inhibitors inhibit the release of the &bgr;-AP4 protein, a potential use was proposed for them as therapeutic agents in Alzheimer's disease (J. Higaki et al., Neuron, 1995, 14, 651-59). Calpain inhibitors also inhibited the release of interleukin-1&agr; (N. Watanabe et al., Cytokine 1994, 6(6), 597-601). In addition, it was found that calpain inhibitors have cytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int.Ass.Breast Cancer Res., Sendai Jp, Sept. 25-28. 1994, Int.J.Oncol. 5(Suppl.), 1994, 381).
Other possible uses of calpain inhibitors are listed in K. K. Wang, Trends in Pharmacol.Sci., 1994, 15, 412-8.
Calpain inhibitors have been described in the literature. However, these are predominantly either irreversible inhibitors or peptide inhibitors. As a rule, irreversible inhibitors are alkylating substances and suffer from the disadvantage that they react nonselectively in the organism or are unstable. Thus, these inhibitors often have undesirable side effects, such as toxicity, and are therefore of limited use or are unusable. Examples of the irreversible inhibitors are E 64 epoxides (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) and 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 or tripeptide aldehydes such as 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 found to be inhibitors of cysteine proteases, in particular calpain. However, only those ketones in which, on the one hand, &agr;-terminal leaving groups cause an irreversible inhibition and, on the other, a carboxylic acid derivative activates the keto group, have been found to be effective inhibitors (see M. R. Angelastro et al., J.Med.Chem. 1990,33, 11-13; WO 92/11850; WO 92,12140; Wo 94/00095 and WO 95/00535). However, only peptide derivatives of these ketoamides and keto esters have so far been reported to be active (Zhao Zhao Li et al., J.Med.Chem. 1993, 36, 3472-80; S. L. Harbenson et al., J.Med.Chem. 1994, 37, 2918-29 and see M. R. Angelastro et al. above).
Ketobenzamides are known in the literature. For example, the keto ester PhCO—Abu—COOCH
2
CH
3
has been described in WO 91/09801, WO 94/00095 and 92/11850. However, M. R. Angelastro et al., in J.Med.Chem. 1990,33, 11-13 found the analogous phenyl derivative Ph—CONH—CH(CH
2
Ph)—CO—COCOOCH
3
to be only a weak inhibitor of calpain. This derivative is also described in J. P. Burkhardt, Tetrahedron Lett., 1988, 3433-36. However, the importance of the substituted benzamides has so far never been investigated.
JP 8183759, JP 8183769, JP 8183771 and EP 520336 describe aldehydes which were derived from dipeptides, with saturated carbocyclic rings, for example cyclohexanes, or saturated heterocyclic rings, for example piperidines, being incorporated into these peptide inhibitors in place of an amino acid, thereby giving rise to novel aldehydes which were calpain inhibitors.
Substituted, non-peptide, heterocyclically substituted benzamide derivatives having an improved effect have now been found.
The present invention relates to heterocyclically substituted benzamides of the formula I
and their tautomeric and isomeric forms, and also, where appropriate, physiologically tolerated salts, where the variables have the following meanings:
R
1
is hydrogen, C
1
-C
6
-alkyl, O—C
1
-C
6
-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, —NHCO-phenyl, —CONHR
8
, NHSO
2
—C
l
-C
4
-alkyl, —NHSO
2
-phenyl, —SO
2
—C
1
-C
4
-alkyl or —SO
2
-phenyl,
R
2
is hydrogen, C
1
-C
6
-alkyl, O—C
1
-C
6
-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, —NHCO-phenyl, —CONHR
8
, NHSO
2
—C
1
-C
4
-alkyl, —NHSO
2
-phenyl, —SO
2
—C
1
-C
4
-alkyl or —SO
2
-phenyl or
R
1
and R
2
are, together, a chain —CH═CH—CH═CH—, which can additionally carry one or two substituents R
6
,
R
3
is hydrogen, chlorine, bromine, fluorine, C
1
-C
6
-alkyl, phenyl, NHCO—C
1
-C
4
-alkyl, NO
2
or NH
2
,
R
4
is C
1
-C
6
-alkyl, which can additionally carry a phenyl cyclopropyl, cyclobutyl, cyclopentyl, cyclophexyl, cycloheptyl, indolyl, pyridyl or naphthyl ring which, for its part, is substituted by one or two radicals R
7
, with R
7
being hydrogen, 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, —CONHR
8
, —NHCO—C
1
-C
4
-alkyl, —NHCO-phenyl, —NHSO
2
-C
1
-C
4
-alkyl, —NHSO
2
-phenyl, —SO
2
—C
1
-C
4
-alkyl or —SO
2
-phenyl,
R
5
is hydrogen, —CO—OR
8
, —CO—NR
9
R
10
,
R
6
is hydrogen, C
1
-C
6
-alkyl, —O—C
1
-C
6
-alkyl, OH, Cl, F, Br, I, CF
3
, NO
2
, NH
2
, CN, COOH, COO—C
1
-C
4
-alkyl,
R
8
is hydrogen or C
1
-C
6
-alkyl,
R
9
is hydrogen or C
1
-C
6
-alkyl which can additionally be substituted by a phenyl ring which can additionally carry a radical R
11
and can be substituted by
R
10
is hydrogen or C
1
-C
6
-al

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