EP0946509A1

EP0946509A1 - Novel heterocyclically substituted benzamides and their use in fighting diseases

Info

Publication number: EP0946509A1
Application number: EP97952007A
Authority: EP
Inventors: Wilfried Lubisch; Achim Möller; Hans-Jörg Treiber
Original assignee: BASF SE
Current assignee: Abbott GmbH and Co KG
Priority date: 1996-12-09
Filing date: 1997-11-28
Publication date: 1999-10-06
Also published as: CA2273988A1; TR199901282T2; HUP0000496A3; US6436949B1; DE19650975A1; AU742732B2; US6172072B1; IL129358A0; CZ292391B6; TW420666B; ZA9710979B; WO1998025899A1; JP2001505889A; ID22490A; SK56699A3; BG63388B1; CO4910161A1; HUP0000496A2; CN1239949A; CZ174399A3

Abstract

The invention concerns heterocyclically substituted benzamides of formula (I) in which R?1, R2, R3, R4, R5¿, X, m and n have the meanings given in the description. The novel compounds are suitable for fighting diseases.

Description

NEW HETEROCYCLICALLY SUBSTITUTED BENZAMIDES AND THEIR APPLICATION FOR COMBATING DISEASES

description

The present invention relates to novel heterocyclically substituted benzamides and their use in combating diseases.

Calpains are intracellular, proteolytic enzymes from the group of so-called cysteine proteases and are found in many cells. Calpains are activated by increased calcium concentration, with a distinction being made between calpain I or μ-calpain, which is activated by μ-molar concentrations of calcium ions, and calpain II or m-calpain, which is activated by m-molar concentrations of calcium ions , distinguishes (P.Johnson, Int. J.Bioche. 1990, 22 (8), 811-22). Today, further calpain isoenzymes are postulated (K.Suzuki et al., Biol.Chem. Hoppe- Seyler, 1995, 376 (9), 523-9).

It is believed that calpains play an important role in various physiological processes. These include cleavages of regulatory proteins such as protein kinase C, cytoskeleton proteins such as MAP 2 and spectrin, muscle proteins, protein breakdown in rheumatoid arthritis, proteins when platelets are activated, neuropeptide metabolism, proteins in mitosis and others, the in. MJBarrett et al. , Life Be. 1991, 48, 1659-69 and K.K. Wang et al. , Trends in Pharmacol. Be . , 1994, 15, 412-9.

Increased calpain levels were measured in various pathophysiological processes, for example: ischemia of the heart (e.g. heart attack), the kidney or the central nervous system (e.g. "stroke"), inflammation, muscular dystrophies, eye cataracts, injuries to the central nervous system (e.g. trauma), Alzheimer's disease, etc. (see KK Wang, above). It is suspected that these diseases are associated with increased and persistent intracellular calcium levels. As a result, calcium-dependent processes are overactivated and are no longer subject to physiological regulation. Accordingly, overactivation of calpains can also trigger pathophysiological processes.

Therefore, it has been postulated that inhibitors of calpain enzymes can be useful in the treatment of these diseases. Various studies confirm this. So Seung-Chyul Hong et al., Stroke 1994, 25 (3), 663-9 and RTBartus et al., Neurological Res. 1995, 17, 249-58 have a neuroprotective effect of Cal - pain inhibitors shown in acute neurodegenerative disorders or ischemia, such as those occurring after a stroke. After experimental brain trauma, calpain inhibitors improved the recovery of the memory deficits and neuromotor disorders that occurred (KESaatman et al. Proc.Natl.Acad. Sci. USA, 1996, 93, 3428-3433). CLEdelstein et al. , Proc.Natl .Acad. Be. USA, 1995, 92, 7662-6, found a protective effect of cal pain inhibitors on kidneys damaged by hypoxia. Yoshida, Ken Ischi et al., Jap.Circ.J. 1995, 59 (1), 40-8, could be cheap

10 Show effects of calpain inhibitors after cardiac damage caused by ischemia or reperfusion. Since calpain inhibitors inhibit the release of the β-AP4 protein, a potential use as a therapeutic agent for Alzheimer's disease has been proposed (J.Higaki et al., Neuron, 1995, 14,

15 651-59). The release of interleukin-lα was also inhibited by calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6 (6), 597-601). Furthermore, it has been found that calpain inhibitors show cytotoxic effects on tumor cells (E.Shiba et al. 20th Meeting Int.Ass. Breast Cancer Res., Sendai Jp, 1994,

20 25-28 Sept., Int.J. Oncol. 5 (Suppl.), 1994, 381).

Further possible uses of calpain inhibitors are in K.K. Wang, Trends in Pharmacol. Be . , 1994, 15, 412-8.

25 calpain inhibitors have already been described in the literature. However, these are predominantly either irreversible or peptide inhibitors. Irreversible inhibitors are generally alkylating substances and have the disadvantage that they react unselectively in the organism or are unstable. So show

30 these inhibitors often have undesirable side effects, such as toxicity, and are therefore restricted or unusable in their use. The irreversible inhibitors include, for example, the epoxides E 64 (E.B. McGowan et al., Biochem. Biophys. Res. Commun. 1989, 158, 432-5), α-haloketones (H. Angliker et al.,

35 J.Med.Chem. 1992, 35, 216-20) and disulfides (R. Matsueda et al., Chem. Lat. 1990, 191-194).

Many known reversible inhibitors of cysteine proteases such as calpain are peptide aldehydes, in particular dipeptide and tripepidic aldehydes such as, for example, Z-Val-Phe-H (MDL 28170) (S.Mehdi, Tends in Biol. Sci. 1991, 16, 150-3) and the compounds from EP 520336.

Peptide ketone derivatives have also been found as inhibitors of 5 cysteine proteases, especially calpain. However, only those ketones in which α-leaving groups cause irreversible inhibition on the one hand and since a carboxylic acid derivative activates the keto group, effective inhibitors are found (see MRAngelastro 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 described as effective (Zhao Zhao Li et al., J.Med.Chem. 1993, 36, 3472-80; SLHarbenson et al., J.Med.Chem. 1994, 37, 2918-29 and see above MRAngelastro et al.).

Ketobenzamides are already known in the literature. The ketoester PhCO-Abu-COOCH ₂ CH _{3 has been described} in WO 91/09801, WO 94/00095 and 92/11850. The analog phenyl derivative Ph-CONH-CH (CH ₂ Ph) -CO-COCOOCH ₃ was described in MRAngelastro et al., J.Med.Chem. 1990, 33, 11-13 found as a weak calpain inhibitor. This derivative is also described in JP Burkhardt, Tetrahedron Lett., 1988, 3433-36. However, the importance of substituted benzamides has never been investigated.

JP 8183759, JP 8183769, JP 8183771 and EP 520336 have described aldehydes derived from dipeptides, with saturated carbocyclic rings, for example cyclohexanes, or saturated heterocyclic rings, for example piperidines, being incorporated into these peptide inhibitors instead of an amino acid, which gave novel aldehydes as calpain inhibitors.

Substituted non-peptide heterocyclic substituted benzamide derivatives with an improved effect have now been found.

The invention relates to heterocyclically substituted benzamides of the formula I.

(R ³ ) _n

and their tautomeric and isomeric forms and, where appropriate, physiologically acceptable salts, in which the variables have the following meaning: Ri hydrogen, -C-C ₆ alkyl, 0-Cι-C ₆ alkyl,, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO-Cι-C ₄ - Alkyl, -NHCO-Cι-C ₄ alkyl, -NHCO-phenyl, -CONHR ⁸ , NHS0 ₂ -Cι-C ₄ alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -Cι-C ₄ alkyl or -S0 ₂ -phenyl,

R ^{2 is} hydrogen, -CC ₆ alkyl, 0 -CC ₆ alkyl,, OH, Cl, F, Br, J, CF ₃ , NO ₂ , NH ₂ , CN, COOH, COO -CC ₄ -Alkyl, -NHCO-Cι-C ₄ alkyl, -NHCO-phenyl, -CONHR ⁸ , NHS0 ₂ -C ₁ -C ₄ alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -Cι-C ₄ alkyl or -S0 ₂ -phenyl or

R ¹ and R ² together form a chain -CH = CH-CH = CH-, which can also carry one or two substituents R ⁶ ,

R ³ hydrogen, chlorine, bromine, fluorine, Ci - C ₆ - alkyl, phenyl, NHCO-C _! -C ₄ alkyl, N0 ₂ , or NH ₂ ,

R ⁴ Ci-Cβ-alkyl, which can also carry a phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylcycloheptyl, indolyl, pyridyl or naphthyl ring, which in turn contains one or two radicals R ^{7 is} substituted, wherein R ^{7 is} hydrogen, -CC ₄ alkyl, -0-C _! -C ₄ -alkyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO-Cι-C ₄ -alkyl, -CONHR ⁸ , -NHCO-Cι-C ₄ - Alkyl, -NHCO-phenyl, -NHS0 ₂ -Cι-C ₄ alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -Cι-C ₄ alkyl or -S0 ₂ -phenyl,

R ⁵ hydrogen f, -CO-OR ⁸ , -CO-NR ⁹ R ¹⁰ ,

or

__ _CO _ _NR IO_ ^V N-R12 ^^

R ^{6 is} hydrogen, -CC ₆ alkyl, -0 -CC ₆ alkyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO-C ₁ -C ₄ alkyl,

R ^{8 is} hydrogen or -CC ₆ alkyl,

R ^{9 is} hydrogen, C ₁ -C ₆ -alkyl, which still has a phenyl ring which can also carry a radical R ¹¹ , and with

-N O -o, 12

can be substituted

Rio hydrogen or -CC ₆ alkyl,

Rii hydrogen, -CC ₆ alkyl, -0 -CC ₆ alkyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO -CC ₄ - Alkyl,

R ^{12 is} hydrogen or a co-alkyl chain which can be substituted by a phenyl ring which itself can also carry one or two R ¹¹ radicals,

X -NH-CO-, -N = CH-, -CH ₂ -CH ₂ -, -CH = CH-, -S0 ₂ -, -CH ₂ -, -CO- and -CH ₂ -C0-,

n is the number 0, 1 or 2 and

m is the number 0, 1, and 2.

Preferred are heterocyclically substituted benzamides of the formula I according to Claim 1, in which R ^{5 is} hydrogen and R 1, R, R 3, R 4, X, m and n have the meaning given above.

Further preferred are heterocyclically substituted benzamides of the formula I according to claim 1, in which R ^{5 is} -CO-NR ⁹ R ¹⁰ and R 1, R 2, R ^3, R 4, X, m and n have the meaning given above.

Finally, preference is also given to heterocyclically substituted benzamides of the formula I according to claim 1, in which R ^{5 is} -CO-OR ⁸ and R 1, R 2, R 3, R 4, X, m and n have the meaning given above.

The compounds of formula I can be used as racemates or as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are desired, these can be obtained, for example, by carrying out a classic resolution with the compounds of the formula I or their intermediates using a suitable optically active base or acid. On the other hand, the enantiomers Compounds can also be prepared by using commercially available compounds, for example optically active amino acids such as phenylalanine, tryptophan and tyrosine.

The invention also relates to the compounds mesomeric and tautomeric to the compounds of the formula I, for example those in which the keto group of the formula I is present as an enol tautomer.

Some of the new compounds I can contain a basic or acidic group. In these cases, the compounds I can be in the form of their physiologically tolerable salts, which can be obtained by reacting the compounds I with a suitable acid or base.

Suitable acids for salt formation with compounds I according to the invention which contain a basic group can be, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid and sulfuric acid. Suitable bases are, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, α, α, α-tris (hydroxymethyl) methylamine and also other amines.

The ketobenzamides I according to the invention can be prepared in various ways, which were outlined in synthesis schemes 1, 2 and 3.

The carboxylic acid esters II are converted into acids III with acids or bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an aqueous medium or in mixtures of water and organic solvents such as alcohols or tetrahydrofuran at room temperature or elevated temperatures, such as 25-100 ° C. The acids III are linked to an α-amino acid derivative, using customary conditions which are described, for example, in Houben-Weyl, Methods of Organic Chemistry, 4th edition, E5, chap. V, and C.R. Lrock, Comprehensive Organic Transformations, VCH Publisher, 1989, Ch.9.

The carboxylic acids III are converted into "activated" acid derivatives R '-COOL, L representing a leaving group such as Cl, imidazole and N-hydroxybenzotriazole, and then by reaction with an amino acid derivative H ₂ N-CH (R4) -COOR converted into the derivative IV. This reaction takes place in anhydrous, inert solvents such as methylene chloride, tetrahydrofuran and dirnethylformamide at temperatures from -20 to + 25 ° C. Scheme 1

The derivatives IV, which are generally esters, are converted into the ketocarboxylic acids V analogously to the hydrolysis described above. In a reaction analogous to the Dakin-West reaction, the keto esters I 'are prepared, using a method by Zhao Zhao Li et al. J.Med.Chem., 1993, 36, 3472-80. A carboxylic acid such as V is reacted with oxalic acid monoester chloride at elevated temperature (50-100 ° C) in solvents such as tetrahydrofuran and then the product thus obtained with bases such as sodium ethanolate in ethanol at temperatures of 25-80 ° C to the ketoester according to the invention I 'implemented. As described above, the keto esters I 'can be hydrolyzed to the ketocarboxylic acids according to the invention.

The conversion to the ketobenzamides I 'is also carried out analogously to the method by Zhao Zhao Li et al. (see above). The keto group in I 'is protected at room temperature by adding 1, 2-ethanedithiol with Lewis acid catalysis, for example with boron trifluoride etherate, in inert solvents, such as methylene chloride, a dithiane being obtained. These derivatives are reacted with amines R ³ -H in polar solvents, such as alcohols, at temperatures from 0-80 ° C., the ketoamides I (R ⁴ = NR ⁷ R ⁸ ) being obtained. Scheme 2

IX

25

An alternative method is shown in Scheme 2. The ketocarboxylic acids III are reacted with a inohydroxycarboxylic acid derivatives VI (preparation of VI see S.L. Harenson et al., J.Med.Chem. 1994, 37, 2918-29) using customary peptide coupling methods (see above,

30 Houben-Weyl) implemented, the amides VII being obtained. These alcohol derivatives VII can be oxidized to the ketocarboxylic acid derivatives I according to the invention. For this one can use various common oxidation reactions (see C.R. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 f.)

35 use, for example, Swern and Swern analog oxidations.

Preference is given to using dimethyl sulfoxide / pyridine-sulfur trioxide complex in solvents such as methylene chloride or tetrahydrofuran, optionally with the addition of dimethyl sulfoxide, at room temperature or at temperatures from -50 to 25 ° C., (T.T. Tidwell, Synthesis

40 1990, 857-70) or sodium hypochlorite / TEMPO (S.L. Harenson et al., See above).

The α-hydroxy esters VII (X = O-alkyl) can be hydrolyzed to carboxylic acids VIII, analogous to the above methods, but preferably with lithium hydroxide in water / tetrahydrofuran mixtures at room temperature. Other esters or amides X are prepared by reaction with alcohols or amines under the coupling conditions already described. The alcohol derivative IX can also be oxidized to the ketocarboxylic acid derivatives I according to the invention.

The aldehydes of the formula I (R ⁵ = hydrogen) according to the invention can be prepared analogously to synthesis scheme 3. Benzoic acid derivatives III are combined with suitable amino alcohols X to give the corresponding benzamides XI. Common peptide coupling methods are used, which are described either in CRLarock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972f. or in Houben-Weyl, Methods of Organic Chemistry, 4th edition, E5, Kap.V. It is preferred to work with "activated" acid derivatives of III, the acid group COOH being converted into a group COL. L represents a leaving group such as Cl, imidazole and N-hydroxybenzotriazole. This activated acid is then reacted with amines to form the iden XI. The reaction takes place in anhydrous, inert solvents such as methylene chloride, tetrahydrofuran and dirnethylformamide at temperatures from -20 to + 25 ° C.

Synthesis scheme 3

XI

reduction

auction

XV XVI The alcohol derivatives XI can be oxidized to the aldehyde derivatives I according to the invention. Various customary oxidation reactions can be used for this (see CRLarock, Comrenhensive Organic Transformations, VCH Publisher, 1989, page 604 f.), Such as Swern- and Swern-analogous oxidations (TTTidwell, Synthesis 1990, 857-70), sodium hypochlorite / TEMPO (SLHarbenson et al., See above) or Dess-Martin (J.Org.Chem. 1983, 48, 4155). It is preferred to work in inert aprotic solvents such as dimethylformamide, tetrahydrofuran or methylene chloride with oxidizing agents such as DMSO / pyridine x SO ₃ or DMSO / oxalyl chloride at temperatures from -50 to + 25 ° C. Alternatively, you can implement the benzoic acid III with aminohydroxamic acid derivatives XΪII to benzamides XIII. The same reaction procedure is used as for the representation of XI. The hydroxam derivatives XIII can also be obtained from the protected amino acids XII by conversion with hydroxylamine. The amide production processes already described are also used here. The protecting group Y ² , for example Boc, is cleaved off in a customary manner, for example using trifluoroacetic acid in methylene chloride. The benzamide-hydroxamic acids XIV 10 thus obtained can be converted into the aldehydes I according to the invention by reduction. For this purpose, for example, lithium aluminum hydride is used as a reducing agent at temperatures from -60 to 0 ° C. in inert solvents such as tetrahydrofuran or ether.

15 Analogously to the last method, it is also possible to prepare benzamide carboxylic acids or acid derivatives, such as esters or amides XV, which can likewise be converted into the aldehydes I according to the invention by reduction. These methods are in R.C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page

20 619-26 listed.

The synthesis of carboxylic acid esters II or carboxylic acids III have in some cases already been described or can be prepared in accordance with conventional chemical methods.

25

For example, precursors II of pyrimidiones I (X = -NH-CO-) can be obtained from the corresponding isatoic anhydrides (see CK Reddy et al., Ind. J. Chem., 1987, 26B, 882) or directly from the 2-aminobenzoates. acid derivatives in sales of phenyl isocyanates (see: CM.

30 Gupta et al., Ind. J. Chem. 1968, 6B, 621; Czech. 128, 433 (CA 70, 115176)).

The analogous pyrimidones (see I and II, X = 35 -NH = CH-) are accessible by condensation of ortho-aminobenzamides with formaldehyde equivalents (see B. Denis et al., J.Med.Chem. 1985, 24 , 531; H.Suesse et al., J. Prakt.Che. 1984, 326, 1027).

Imides (X = -C0-, or -CH ₂ -CO-) can be synthesized from the corresponding anhydrides of dicarboxylic acids (see:

40 J.M. Chapman et al. , J.Med.Chem. 1983, 26, 237; K. Pinney et al., J.Org.Chem., 1991, 56, 3125; IY.Imai et al., Nippon Kagaku Kaishi 1975, 2954 (CA 84, 105522)). The phthalazinones (X = -CH = N-) can be prepared from phenylhydrazines and ortho-substituted benzoic acid derivatives (see: J.E. Francis et al., Can.J.Chem.

45 1982, 60, 1214). Lactams (X = -CH ₂ -; -CH ₂ -CH ₂ -) are accessible, for example, from the imides by reduction (see: J.Brewster et al., J.Org.Chem. 1963, 28, 501; GB 2204579; R.Sato et al. , Bull. Chem. Soc. Jpn, 1988, 61, 2238).

The ketobenzamides I according to the invention are inhibitors of cysteine proteases, in particular of cysteine proteases such as calpaine I and II and cathepsine B and L.

The inhibitory effect of the ketobenzamides I was determined using enzyme tests customary in the literature, a concentration of the inhibitor at which 50% of the enzyme activity is inhibited being determined as the yardstick 10 (= IC ₅₀ ). A Ki value was also determined in some cases. The ketobenzamides I were measured in this way for their inhibitory effect on calpain I, calpain II and cathepsin B.

15

Cathepsin B test

Cathepsin B inhibition was determined analogously to a method by S.Hasnain et al., J.Biol.Chem. 1993, 268, 235-40.

20th

2μL of an inhibitor solution prepared from inhibitor and DMSO (final concentrations: 100μM to 0.01μM) are added to 88μL cathepsin B (cathepsin B from human liver (Calbiochem), diluted to 5 units in 500μM buffer). This mixture is preincubated for 60 min 25 at room temperature (25 ° C.) and the reaction is then started by adding 10 μl 10 mm Z-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is monitored for 30 min at 405 nm in the microtiter plate reader. The ICso's are then determined from the maximum gradients.

30

Calpain I and II test

The inhibitory properties of calpain inhibitors are tested in buffer with 50 mM Tris-HCl, pH 7.5; 0.1 M NaCl;

35 1 mM dithiotreithol: 0.11 mM CaCl ₂ , the fluorogenic calpain substrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachern / Switzerland) being used (Sasaki et al. J. Biol. Chem. 1984 , Vol. 259, 12489-12494). Human μ-calpain is made from erythrocytes based on the methods of Croall and DeMartino (BBA 1984, Vol. 788,

40 348-355) and Graybill et al. (Bioorg. & Med. Lett. 1995, Vol. 5, 387-392). After several chromatographic steps (DEAE-Sepharose, Phenyl-Sepharose, Superdex 200 and Blue-Sepharose), the enzyme is obtained with a purity of <95%, assessed according to SDS-PAGE, Western blot analysis and N-terminal sequences

45 ornament. The fluorescence of the cleavage product 7 -amino- -methyl-o-marine (AMC) is monitored in a Spex-Fluorolog fluorimeter at λ _Pv = 380 nm and λ _em = 460 nm. In a measuring range of The cleavage of the substrate is linear for 60 min and the autocatalytic activity of calpain is low if the experiments are carried out at temperatures of 12 ° C. (see Chatterjee et al. 1996, Bioorg. & Med. Chem. Lett., Vol 6, 1619-1622). The inhibitors and the calpain substrate are added to the test batch as DMSO solutions, the final concentration of DMSO not exceeding 2%.

In a typical experiment, 10 μl of substrate (250 μm final) and then 10 μl of μ-calpain (2 μg / ml final, ie 18 nM) are added to a 1 ml cuvette that contains buffer. The calpain-mediated cleavage of the substrate is measured for 15 to 20 min. Then add 10 μl inhibitor (50 or 100 μM solution DMSO) and measure the inhibition of the cleavage for a further 40 min. Ki values are determined according to the usual equation for reversible inhibition, ie K: = l (v ₀ / v) -l; where I = inhibitor concentration, v ₀ = initial rate before adding the inhibitor; Vi = reaction rate in equilibrium.

Calpain is an intracellular cysteine protease. Calpain inhibitors must pass through the cell membrane to prevent the breakdown of intracellular proteins by calpain. Some known calpain inhibitors, such as E 64 and leupeptin, only poorly cross the cell membranes and accordingly, although they are good calpain inhibitors, show only poor activity on cells. The aim is to find connections with better membrane passage. We use human platelets as evidence of the membrane passage of calpain inhibitors.

Calpain-mediated breakdown of the tyrosine kinase pp60src in platelets

_{A fter} the activation of platelets, the tyrosine kinase pp60src was cleaved by calpain. This was done by Oda et al. in J. Biol. Chem., 1993, Vol 268, 12603-12608. It was shown that the cleavage of pp60src can be prevented by calpeptin, an inhibitor for calpain. Based on this publication, the cellular effectiveness of the new substances was tested. Fresh human blood with citrate was centrifuged at 200 g for 15 min. The platelet-rich plasma was pooled and diluted 1: 1 with platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KC1, 0.5 mM MgCl ₂ × 6 H ₂ O, 0.24 mM NaH ₂ PO ₄ × H ₂ 0, 12 mM NaHC0 ₃ , 5.6 mM glucose, 1 mM EDTA, pH 7.4). After a centrifugation and washing step with platelet buffer, the platelets were adjusted to 10 ⁷ cells / ml. The human platelets were isolated at RT. In the test mixture, isolated platelets (2 × 10 ⁶ ) with different concentrations of inhibitors (dissolved in DMSO) were preincubated for 5 min at 37 ° C. The platelets were then activated with 1 μM Ionophore A23187 and 5 mM CaCl ₂ . After 5 min incubation, the platelets were briefly centrifuged at 13000 rpm and the pellet was taken up in SDS sample buffer (SDS sample buffer: 20 mM Tris-HCl, 5 mM EDTA, 5 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 5 μg / ml leupeptin, 10 μm pepstatin, 10% glycerin and 1% SDS). The proteins were separated in a 12% gel and pp60src and its 52-kDa and 47-kDa cleavage products were identified by Western blotting. The rabbit anti-Cys-src (pp60 ^c " ^src ) polyclonal antibody used had been purchased from Biomol Feinchemischen (Hamburg). This primary antibody was detected with an HRP-coupled second goat antibody (Boehringer Mannheim, FRG) Western blotting was carried out according to known methods.

The cleavage of pp60src was quantified densitometrically, using controls which were not activated (control 1: no cleavage) and plates treated with ionophore and calcium (control 2: corresponds to 100% cleavage). The ED 50 value corresponds to the concentration of inhibitor at which the intensity of the color reaction of the 60 kDa band corresponds to the value intensity of control 1 plus control 2 divided by 2.

It is postulated that calpain also plays a role in apoptotic cell death (M.K.T. Squier et al. J. Cell. Physiol. 1994, 159, 229-237; T. Patel et al. Faseb Journal 1996, 590, 587-597). Therefore, in another model, cell death was triggered with calcium in the presence of a calcium ionophore in a human cell line. Calpain inhibitors must enter the cell and inhibit calpain there to prevent cell death.

Calcium-mediated cell death in NT2 cells

In the human NT2 cell line, cell death can be triggered by calcium in the presence of the ionophore A 23187. 10 ⁵ cells / well are plated in microtiter plates 20 h before the experiment. After this period, the cells are incubated with various concentrations of inhibitors in the presence of 2.5 μM ionophore and 5 mM calcium. After 5 h, 0.05 ml of XTT (Cell Proliferation Kit II, Boehringer Mannnheim) are added to the reaction mixture. The optical density is determined approximately 17 hours later, in accordance with the manufacturer's instructions, in the EASY READER EAR 400 from SLT. The optical density at which half of the cells have died is calculated from the two measured values without Inhibitors incubated in the absence and presence of ionophore.

A number of neurological diseases or mental disorders result in increased glutamate activity, which leads to states of overexcitation or toxic effects in the central nervous system (CNS).

Substances that inhibit the effects mediated by glutamate can thus be used to treat these diseases. Glutamate antagonists, including in particular NMDA antagonists or their modulators and the AMPA antagonists, are suitable for therapeutic use as agents against neurodegenerative diseases (Huntington's and Parkinson's diseases), neurotoxic disorders after hypoxia, anoxia or Ischemia, as it occurs after "Stroke", or also as anti-epileptics, antidepressants and anxiolytics (cf. Medicinal Research 1990, 40, 511 - 514; TIPS, 1990, 11, 334 - 338 and Drugs of the Future 1989, 14 (11), 1059-1071).

The intracerebral application of excitatory amino acids (= EAA = Excitatory Amino Acids) induces such a massive overexcitation that it leads to cramps and the death of the animals in a short time. Through systemic - e.g. intraperitoneal - administration of centrally acting EAA antagonists can inhibit these symptoms. Since the excessive activation of EAA receptors of the central nervous system plays an important role in the pathogenesis of various neurological diseases, it can be concluded from the proven EAA antagonism in vivo that the substances can be used therapeutically against such CNS diseases. These include focal and global ischemia, trauma, epilepsy and various neurodegenerative diseases such as Huntington's disease, Parkinson's disease and others

It has already been shown that calpain inhibitors in cell cultures also have a protective action against cell death caused by EAA (H. Cauer et al., Brain Research 1993, 607, 354-356; Yu Cheg and AY Sun, Neurochem. Res 1994, 19, 1557-1564). The calpain inhibitors contained in this application are surprisingly effective even against the cramps caused by EAA (eg NMDA or AMPA) and thus indicate therapeutic use in the above-mentioned CNS diseases. Glutamate-induced cell death on cortical neurons

As with Choi D.W., Maulucci-Gedde M.A. and Kriegstein A.R., the test was "Glutamate neurotoxicity in cortical cell culture". J. Neurosci. 1989, 7, 357-368.

The cortex halves are prepared from 15-day-old mouse embryos and the individual cells are obtained enzymatically (trypsin). These cells (glia and cortical neurons) are sown in 24 well plates. After three days (laminin coated plates) or seven days (ornithine coated plates) the mitosis treatment is carried out with FDU (5-fluoro-2-deoxyuridine). 15 days after cell preparation, cell death is triggered by adding glutamate (15 min). After the glutamate removal, the calpain inhibitors are added. 24 hours later, cell damage is determined by determining lactate dehydrogenase (LDH) in the cell culture supernatant.

The benzamides of the formula I are inhibitors of cysteine proteases such as in particular calpain I or II and cathepsin B or L and can thus be used to combat diseases which are associated with increased enzyme activity of the calpain enzymes or cathepsin enzymes , serve. They are therefore suitable for the treatment of neurodegenerative diseases which occur after ischemia, trauma, subarachnoidal bleeding and stroke and which include, in particular, stroke and head trauma, and of neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease and Huntington's disease and also for treatment damage to the heart after cardiac ischemia, damage to the kidneys after renal ischemia, skeletal muscle damage, muscular dystrophies, damage caused by proliferation of smooth muscle cells, coronary vasospasm, cerebral vasospasm, cataracts of the eyes, restenosis of the bloodstream after angioplasty. In addition, the benzamides of formula I can be useful in chemotherapy of tumors and their metastases and for the treatment of diseases in which an increased level of interleukin-1 occurs, such as inflammation and rheumatic diseases.

In addition to the usual pharmaceutical auxiliary substances, the pharmaceutical preparations according to the invention contain a therapeutically effective amount of the compounds I.

For local external use, for example in powders, ointments or sprays, the active compounds can be present in the usual concentrations. As a rule, the active ingredients are in an amount of 0.001 to 1% by weight, preferably 0.01 to 0.1

% By weight.

For internal use, the preparations are administered in single doses. 0.1 to 100 mg per kg body weight are given in a single dose. The preparations can be administered daily in one or more doses depending on the type and severity of the diseases.

In accordance with the desired type of application, the pharmaceutical preparations according to the invention contain, in addition to the active ingredient, the customary carriers and diluents. For local external use, pharmaceutical-technical auxiliaries, such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, paraffin oil, petroleum jelly and wool fat, can be used. Milk sugar, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable for internal use.

Antioxidants such as tocopherol and butylated hydroxyanisole and butylated hydroxytoluene, taste-improving additives, stabilizers, emulsifiers and lubricants can also be present.

The substances contained in the preparation in addition to the active substance and the substances used in the manufacture of the pharmaceutical preparations are toxicologically harmless and compatible with the respective active substance. The pharmaceutical preparations are produced in a customary manner, for example by mixing the active ingredient with other customary excipients and diluents.

The pharmaceutical preparations can be administered in various modes of administration, for example orally, parenterally or intravenously by infusion, subcutaneously, intraperitoneally and topically. Forms of preparation such as tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays are possible.

Examples

example 1

2- (4- (N- (S) -3-Phenyl-propan-l-al-2-yl) carbamoylphenyl) benzo [g] phthalimide a) 2- (4-Ethoxycarbonylphenyl) benzo [g] phthalimide

10 g (50 mmol) of naphthalene-2, 3-dicarboxylic anhydride and 8.3 g (50 mmol) of ethyl 3-amino-benzoate were heated to 90 ° C. in 50 ml of n-butanol for 16 h. The mixture was allowed to cool and then the precipitate which had precipitated was filtered off with suction. Yield: 8.4g (48%).

b) 2- (4-carboxyphenyl) benzo [glphthalimide

7.6 g (22 mmol) of the intermediate compound la were dissolved in 100 ml of ethanol and, after addition of 50 ml of 2M sodium hydroxide solution, stirred for 16 hours at room temperature. The organic solvent was removed in vacuo and the aqueous residue was acidified with 1M hydrochloric acid. The precipitate that formed was filtered off with suction. Yield: .. 7.2g (100%) _.

c) 2- (4- (N- (S) -3-Phenyl-propan-l-ol-2-yl) carbamoylphenyl) benzo [g] phthalimide

To 2.4 g (7.5 mmol) of the intermediate compound Ib and 1.1 g (7.5 mmol) (S) -3-phenylalaninol in 50 ml of anhydrous methylene chloride were added in succession 1.9 g (18.8 mmol) of triethylamine, 25 ml of dimethyl sulfoxide and 0.34 g (2.5 mmol) 1- Hydroxybenzotriazole (HOBT) added. 1.4 g (7.5 mmol) of 3- (3-dimethylaminopropyl) -1-ethyl-carbodiimide hydrochloride (EDC) were then added at 0.degree. Everything was stirred for 1 hour at 0 ° C. and then for 16 hours at room temperature. The organic solvent was then removed in vacuo and the residue was diluted with 500 ml of water. The precipitate was filtered off and purified by chromatography (eluent: methylene chloride / methanol / triethylamine = 3/1/1), 1.0g (30%) of the product being obtained.

d) 2- (4- (N- (S) -3-Phenyl-propan-l-al-2-yl) carbamoylphenyl) benzo [g] phthalimide

To 0.8 g (1.8 mmol) of the intermediate lc and 0.73 g (7.2 mmol) of triethylamine in 20 ml of anhydrous dimethyl sulfoxide, 1.15 g (7.2 mmol) of pyrididine-sulfur trioxide complex, dissolved in 20 ml of dimethyl sulfoxide, were added at room temperature. Everything was stirred for 16 hours at room temperature. The reaction mixture was poured onto 500 ml of water and the precipitate obtained was suction filtered. Yield: 0.7g (89%).

1H-NMR (D ₆ -DMSO): δ = 3.0 (1H), 3.3 {1H), 4.5 (1H), 7.1-8.4 (13H), 8.6 (2H), 9.0 (1H) and 9.6 (1H) ppm

Example 2

6,7-dimethoxy-3- (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

a) 6, 7-Dimethoxy-3 (4-ethoxycarbonylphenyl) benzopyrimidione

To 17 g (80.5 mmol) of 2-amino-4, 5-dimethoxy-benzoic acid methyl ester and a spatula tip of 4-dimethylaminopyridine in 250 ml of anhydrous dimethylformamide were added at room temperature

Add 15.4 g (80.5 mmol) of 4-ethoxycarbonylphenyl isocyanate in portions. Then everything was stirred at 100 ° C. for 1 hour. The solvent was removed in vacuo and the residue was heated to 180 ° C. The reaction mixture crystallized after a while. The solid was then treated with acetone and suction filtered. The solid was recrystallized from dimethylformamide, 21.5 g (73%) of the product being obtained.

b) 3- (4-carboxyphenyl) -6, 7-dimethoxy-benzopyrimidione

21.5 g (58 mmol) of the intermediate 2a were suspended in 100 ml of tetrahydrofuran, and 5.6 g (0.32 mol) of lithium hydroxide, dissolved in 300 ml of water, were added. Everything was stirred for 2 hours at room temperature. The reaction solution was then acidified with 15 ml of glacial acetic acid and the organic solvent was removed in vacuo. The resulting precipitate was filtered off, giving 20.3 g (100%) of the product.

c) 6,7-Dimethoxy-3- (4- (N- (S) -3-phenyl-propan-l-ol-2-.yl) carbamoyl-phenyl) benzopyrimidione 2g (5.8mmol) of the intermediate compound 2b were reacted analogously to Example 1c in a solvent mixture of dimethylfor amide and dimethyl sulfoxide. Yield: 2.3g (83%).

d) 6,7-Dimethoxy-3- (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoyl-phenyl) benzopyrimidione

2.1 g (4.4 mmol) of the intermediate compound were oxidized analogously to Example ID. Yield: 0.65g (35%).

MS: M / e = 473 (M ⁺ ).

Example 3

2- (4-Methyl-3 (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoyl-phenyl) -benzo [g] phthalimide

a) 2-Methyl-5-nitro-N (- (S) -3-phenyl-propan-2-yl-3-ol) -benzamide

2.6 ml (27.6 mmol) of ethyl chloroformate, dissolved in 30 ml of tetrahydrofuran, were added dropwise to 5 g (27.6 mmol) of 2-methyl-5-nitrobenzoic acid and 4.2 ml (30.4 mmol) of triethylamine in 70 ml of anhydrous tetrahydrofuran at 0 ° C. Everything was stirred for 1 hour at room temperature. Then 4.2 g (27.6 mmol) of (S) -3-phenylalaninol were added and the mixture was stirred at room temperature for 16 h. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with aqueous sodium bicarbonate solution, water, dilute hydrochloric acid and again with water, dried and concentrated in vacuo. The residue was treated with ether and suction filtered. 7.5 g (87%) of the intermediate compound were obtained.

b) 5-Amino-2-methyl-N- ((S) -3-phenyl-propan-2-yl-3-ol) -benzamide

6.3 g (20 mmol) of the intermediate 3a were dissolved in 200 ml of ethanol / tetrahydrofuran (3/1) and after the addition of 0.5 g.

Palladium / carbon (10%) hydrogenated. Then it was filtered and the filtrate was concentrated in vacuo. The residue was treated with ether and suction filtered. Yield: 4.9g (86%).

c) 2- (4-Methyl-3 (N- (S) -3-phenyl-propan-1-ol-2-yl) carbamoyl-phenyl) -benzo [g] phthalimide

0.76 g (4 mmol) of the intermediate compound 3b were reacted with naphthalene-2, 3-dicarboxylic anhydride analogously to Example 1a, 0.59 g (48%) of the product being obtained.

d) 2- (-Methyl-3 (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoyl-phenyl) -benzo [g] phthalimide

0.42g (0.9mmol) of the intermediate 3c was oxidized analogously to example Id. Yield: 0.34g (81%).

1H-NMR (D ₆ -DMSO): δ = 2.2 (3H), 2.8 (1H), 3.4 (1H), 4.7 (1H), 7.1-7.6 (8H), 7.8 (2H), 8.3 (2H), 8.6 (2H), 8.8 (1H) and 9.7 (1H) ppm.

Example 4

2- (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) methylbenzo [g] phthalimide

a) 2 (4-Ethoxycarbonylphenyl) methyl-benzo [g] phthalimide

1.7 g (10 mmol) of 4-aminomethylbenzoic acid ethyl ester hydrochloride and 2.0 g (20 mmol) of triethylamine in 25 ml of PEG400 were stirred at room temperature for 15 min. Thereafter, 2 g (10 mmol) of 2,3-naphthalenedicarboxylic acid anhydride were added and the mixture was heated to 100 ° C. for 2 hours. The reaction mixture was then added to water and the precipitate was filtered off with suction. 2.3 g (68%) of the intermediate compound were obtained.

b) 2 (4-carboxyphenyl) methyl-benzo [g] phthalimide 2g (5.8 mol) of the intermediate compound 4a were saponified analogously to Example 1b. Yield: 1.9g (98%).

c) 2- (4- (N- (S) -3-Phenyl-propan-l-ol-2-yl) carbamoylphenyl) methylbenzo [g] phthalimide

1.3 g (4 mmol) of the intermediate compound 4b were reacted analogously to Example 1c. Yield: 0.65g (35%).

d) 2- (4- (N- (S) -3-Phenyl-propan-l-al-2-yl) carbamoylphenyl) methyl-benzo [g] phthalimide

0.33 g (0.7 mmol) of the intermediate 4c were oxidized analogously to Example 1d. Yield: 0.3g (97%).

MS (ESI): m / e = 462 (M ⁺ )

Example 5

3- (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) -naph- r [Γc> 1]

a) 3- (4-Ethoxycarbonylphenyl) naphtho [c] pyrimidione

1.4 g (7 mmol) of ethyl 3-aminonaphthoate, 1.34 g (7 mmol) of 4-ethoxyphenyl isocyanate and a spatula tip of 4-dimethylaminopyridine were boiled under reflux in 30 ml of tetrahydrofuran for 4 hours. Then everything was concentrated in vacuo, the residue was boiled with ethanol and suction filtered. Yield: 1.7g (67%).

b) 3- (4-carboxyphenyl) naphtho [c] pyrimidione

1.6 g (4.4 mmol) of the intermediate compound 5a were added to 30 ml of tetrahydrofuran, 0.8 g (28.9 mmol) of lithium hydroxide, dissolved in 30 ml of water, 12 ml of 2 ml of 2M sodium hydroxide solution and 30 ml of ethanol were added and the mixture was stirred at room temperature for 1 hour. The organic solvent was concentrated in vacuo, the remaining aqueous phase was diluted and diluted with acidified to pH about 2-3. The precipitate was filtered off with suction, 1.4g (96%) of the product being obtained.

c) 3- (4- (N- (S) -3-Phenyl-propan-1-ol-2-yl) carbamoylphenyl) naphtho [c] pyrimidione

1.3 g (4 mmol) of the intermediate compound 5b were reacted analogously to Example 1c. Yield: 1.1g.

d) 3- (4- (N- (S) -3-Phenyl-propan-l-al-2-yl) carbamoylphenyl) naphtho [c] pyrimidione

0.9 g (2 mmol) of the intermediate compound 5c were oxidized analogously to Example 1d, with 0.65 g (72%) of the product being obtained.

1H-NMR (D ₆ -DMSO): 5 = 2.95 (1H), 3.2 (1H), 4.5 (1H), 7.1-8.K1H), 8.7 (1H), 9.0 (1H), 9.6 (1H) and 11.7 (lH) ppm.

Example 6

3- (4- (N- ((S) -l-carbamoyl-l-oxo-3-phenyl-propan-2-yl) carbamoylphenyl) -naphtho [c] pyrimidione

a) 3- (4- (N- (2 (S) -l-Carbamoyl-1-hydroxy-3-phenyl-propan-2-yl) carbamoylphenyl) -naphtho [c] pyrimidione

1.2 g (3.6 mmol) of the intermediate compound 5b were prepared analogously to Example 1c with 1.1 g (3.6 mmol) of 0- (tert-butyl) -2 (S) -N (l-carboxy-2-hydroxy-3-phenyl- propan-l-ol-2-yl) carbamate (SLHarbeson et al., J.Med.Chem. 1994, 37, 2918-29). Yield: 1.2g (66%).

b) 3- (4- (N- ((S) -l-carbamoyl-l-oxo-3-phenyl-propan-2-yl) carbamoylphenyl) -naphtho [c] pyrimidione

1.1 g (2.2 mmol) of the intermediate compound 6b were oxidized analogously to example Id. Yield: 0.93g (90%). MS: m / e = 506 (M ⁺ ).

Example 7

8-methyl-3- (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

a) 3- (4-Ethoxycarbonylphenyl) -8-methyl-benzopyrimidione

20 g (0.12 mol) of methyl 2-amino-5-methylbenzoate were reacted with 4-ethoxycarbonylphenyl isocyanate analogously to Example 2a. Yield: 30.1g (77%).

b) 3- (4-carboxyphenyl) -8-methyl-benzopyrimidione

29 g (89.4 mmol) of the intermediate compound 7a were hydrolyzed analogously to example 2b, 21.3 g (81%) of the product being obtained.

c) 8-Methyl-3- (4- (N- (S) -3-phenyl-propan-1-ol-2-yl) carbamoylphenyl) benzopyrimidione

2 g (6.8 mmol) of the intermediate 7b were reacted analogously to Example 1c. Yield: 1.5g (52%).

d) 8-Methyl-3- (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

1.3 g (3.0 mmol) of the intermediate 7c were reacted analogously to Example 2d. Yield: 1.2g (93%).

1H-NMR (D ₆ -DMSO): δ = 2.4 (3H), 3.0 (1H), 3.4 (1H), 4.5 (1H), 7.0-8.0 (12H), 9.0 (1H), 9.6 (1H) and 11.9 (lH) ppm.

Example 8

3- (4- (N- (S) -3-Phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

a) 3- (4-Ethoxycarbonylphenyl) benzopyrimidione

19g (O.lMol) propyl 2-aminobenzoate were reacted with 4-ethoxycarbonylphenyl isocyanate analogously to Example 2a, 12.2g (32%) of the product being obtained.

b) 3- (4-carboxyphenyl) benzopyrimidione

30 g (92.5 mmol) of the intermediate compound 8a were hydrolyzed analogously to Example 2b. Yield: 25.1g (92%).

c) 3- (4- (N- (S) -3-Phenyl-propan-l-ol-2-yl) carbamoylphenyl) benzopyrimidione

2g (7.1 mmol) of the intermediate compound 8b were reacted analogously to Example 1c. Yield: 2.6g (88%).

d) 3- (4- (N- (S) -3-Phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

2.3g (55.4mmol) of the intermediate compound 8c were implemented analogously to example ld. Yield: 1.7g (74%).

IH-NMR (D ₆ -DMSO): δ = 3.0 (1H), 3.3 (1H), 4.5 (1H), 7.0-8.0 (13H), 9.0 (1H), 9.7 (1H) and 11.6 (1H) ppm.

Example 9

6-methyl-3 (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

a) 3- (4-Ethoxycarbonylphenyl) -6-methyl-benzopyrimidione

20 g (0.12 mol) of methyl 2-amino-5-methylbenzoate were reacted with 4-ethoxycarbonylphenyl isocyanate analogously to Example 2a, 30.1 g (77%) of the product being obtained.

b) 3- (4-carboxyphenyl) -6-methyl-benzopyrimidione

30 g (92.5 mmol) of the intermediate compound 9a were hydrolyzed analogously to example 2b. Yield: 25.1g (92%).

c) 6-Methyl-3 (4- (N- (S) -3-phenyl-propan-l-ol-2-yl) carbamoylphenyl) benzopyrimidione

2 g (6.8 mmol) of the intermediate compound 9b were reacted analogously to Example 1c. Yield: 1.2g (42%).

d) 6-Methyl-3 (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

1.0 g (2.3 mmol) of the intermediate compound 9c were reacted analogously to example ld. Yield: O.73g (73%).

IH-NMR (D ₆ -DMSO): δ = 2.4 (3H), 3.0 (1H), 3.3 (1H), 4.5 (1H), 7.0-8.0 (12H), 9.0 (1H), 9.7 (1H) and 11.5 (broad) ppm.

Example 10

7-chloro-3 (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

a) 7-Chloro-3 (4-ethoxycarbonylphenyl) benzopyrimidione

16 g (86.2 mmol) of methyl 2-amino-4-chlorobenzoate were reacted with 4-ethoxycarbonylphenyl isocyanate analogously to Example 2a, 12.1 g (41%) of the product being obtained.

b) 3- (4-carboxyphenyl) -7-chloro-benzopyrimidione 12 g (34.8 mmol) of the intermediate compound 10a were hydrolyzed analogously to Example 2b. Yield: 10.1g (91%).

c) 7-Chloro-3 (4- (N- (S) -3-phenyl-propan-1-ol-2-yl) carbamoylphenyl) benzopyrimidione

2g (6.3 mmol) of the intermediate compound 10b were reacted analogously to Example 1c. Yield: 1.7g (60%).

d) 7-chloro-3 (4- (N- (S) -3-phenyl-propan-l-al-2-yl) carbamoylphenyl) benzopyrimidione

1.3 g (28.9 mmol) of the intermediate compound 10c were reacted analogously to example Id. Yield: 1.1g (86%).

IH-NMR (D ₆ -DMS0): δ = 3.0 (1H), 3.3QH), 4.5 (1H), 7.0-8.0 (12H), 9.0 (1H), 9.7 (IH) and 11.7 (lH) ppm.

The following were prepared as in Examples 1-10:

Example 11

3- (4- (N- (S) -Pent-1-al-2-yl) carbamoylphenyl) naphtho [c] yrimidione

H

! H NMR (D ₆ -DMSO): δ = 0.9 (3H), 1.45 (2H), 1.7 (IH), 1.9 (IH), 4.3 (IH), 7.4-7.8 (5H), 7.9-8.2 (4H), 8.7 (IH), 9.0 (IH), 9.6 (IH), 11.7 (IH). Example 12

3- (4- (N- (S) -cyclohexylprop-1-al -2-yl) carbamoylphenyl) naphtho [c] pyrimidione

H

iH- MR (D ₆ -DMSO): δ = 0.8-2.0 (13H), 4.4 (IH), 7.4-7.7 (5H), 7.8-8.2 (4H), 8.7 (IH), 9.6 (IH), 11.7 ( IH).

Example 13

3- (4- (N- (S) -Ethylcarbamoyl-l-oxo-3-phenylpropan-2-yl) carbamoylphenyl) -naphtho [c] pyrimidione

MS m / e = 534 (M ⁺ ) Example 14

3- (4- (N- (S) - (1- (2-pyridyl) ethylcarbamoyl - 1-oxo-3-phenyl-propan-2yl) carbamoylphenyl) -naphtho [c] pyrimidione

MS m / e = 611 (M ⁺ )

Example 15

3- (4- (N- (S) -3 - Phenylprop-1-al-2-yl) carbamoylphenyl) pyrazino [b] pyrimidione

H! H NMR (D ₆ -DMSO): δ = 2.8-3.0 (2H), 4.5 (IH), 7.2-7.7 (5H), 7.6-7.9 (4H), 8.15 (1H9; 8.2) (IH), 8.8 (IH), 9.6 (IH). Example 16

3- (4- (N- (S) - 3 -phenylprop-1-al-2-yl) carbamoylphenyl) dichloropyrazino [b] pyrimidione

iH-NMR (De-DMSO): δ = 2.9 (IH), 3.2 (IH), 4.4 (IH), 7.1 (5H), 7.5 (2H), 7.7 (2H), 8.8 (IH), 9.05 (IH) , 9.6 (IH).

Example 17

5,7-dimethyl-3- (4- (N- (S) -3 - phenylprop-1-al -2 -yl) carbamoylphenyl) pyidino [b] pyrimidione

iH-NMR (D ₆ -DMSO): δ = 2.45 (3H), 2.6 (3H), 3.0 (IH), 3.3 (IH), 3.3 (IH, 4.5 (IH), 7.01 (IH), 7.2-7.5 ( 7H), 7.9 (2H), 9.0 (IH), 9.6 (IH), approx. 12 (IH). Example 18

3 - (4- (N- (S) -3 - (2-pyridyl) prop-1-al-2 -yl) carbamoylphenyl) naphtho [c] pyrimidione

H

IH-NMR (De-DMSO): δ = 2.8-3.3 (2H), 4.6 (IH), 7.2-8.2 (11H), 8.5 (IH), 8.7 (2H), 9.1 (IH), 9.6 (IH), 11.8 (broad, IH).

Example 19

3- (4- (N- (S) -3-phenylprop-l-al-2-yl) carbamoylphenyl) pyidino [c] pyrimidione

H

MS m / e = 414 (M ⁺ )

The following can be produced analogously:

If only one number is given for X ¹ , this means the position of the heterocyclic ring system on the phenyl ring.

Claims

claims

1. Heterocyclically substituted benzamides of the formula I

and their tautomeric and isomeric forms and, if appropriate, physiologically tolerable salts, in which the variables have the following meaning:

R ^{1 is} hydrogen, -CC ₆ alkyl, 0 -CC ₆ alkyl,, OH, Cl, F, Br, J, CF ₃ , NO ₂ , NH ₂ , CN, COOH, COO -CC ₄ -Alkyl, -NHCO-C ₁ -C ₄ alkyl, -NHCO-phenyl, -CONHR ⁸ , NHS0 ₂ -Cι-C ₄ alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -Cι-C ₄ alkyl or - S0 ₂ -phenyl,

R ^{2 is} hydrogen, -CC ₆ alkyl, 0 -CC ₆ alkyl,, OH, Cl, F, Br, J, CF ₃ , NO ₂ , NH ₂ , CN, COOH, COO -CC ₄ -Alkyl, -NHCO-Cι-C ₄ alkyl, -NHCO-phenyl, -CONHR ⁸ , NHS0 ₂ -Cι-C ₄ alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -Cι-C ₄ alkyl or - S0 ₂ -phenyl or

R ^{3 is} hydrogen, chlorine, bromine, fluorine, Ci-Cε-alkyl, phenyl, NHCO-Ci-C-alkyl, N0 ₂ , or NH _{2 (}

R ⁴ Ci-Cβ-alkyl, which can also carry a phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indolyl, pyridyl or naphthyl ring, which in turn is substituted by one or two radicals R ⁷ , where R ^{7 is} hydrogen, C 1 -C ₄ -alkyl, -0-C 1 -C ₄ -alkyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO-Cι-C ₄ - Alkyl, -CONHR ⁸ , -NHCO -CC-C-alkyl, -NHCO-phenyl, -NHS0 ₂ -C _x -C ₄ -alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -Cι-C ₄ -alkyl or - S0 ₂ -phenyl, R5 hydrogen, -CO-OR ⁸ , -CO-NR ^ R ⁱ o,

or

- CO-NR ⁰ - (NR ¹²

R6 is hydrogen, -CC ₆ alkyl, -0 -CC ₅ alkyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO-C _! -C ₄ -, alkyl,

R ^{8 is} hydrogen or Ci-Cβ-alkyl,

R ^{9 is} hydrogen, Ci-Cε-alkyl, which also has a phenyl ring which can also carry a radical R ¹¹ , and with

^ Λ -> 12

—N O

can be substituted

R ^{10 is} hydrogen or -CC ₆ - alkyl,

R ^{11 is} hydrogen, -CC ₆ alkyl, -0 -CC ₆ alkyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO -CC ₄ -Alkyl,

R ^{12 is} hydrogen or a -C ₄ alkyl chain which can be substituted by a phenyl ring which itself can also carry one or two R ¹¹ radicals,

X -NH-CO-, -N = CH-, -CH ₂ -CH ₂ -, -CH = CH-, -S0-, -CH ₂ -, -CO- and -CH ₂ -CO-,

n is the number 0, 1 or 2 and

m is the number 0, 1, and 2,

2. Heterocyclically substituted benzamides of the formula I according to claim 1, wherein

R ^{5 is} hydrogen and

R ¹ , R ² , R ³ , R ⁴ , X, m and n have the meaning given in claim 1.

3. Heterocyclically substituted benzamides of the formula I according to claim 1, in which

R ⁵ -CO-NR ⁹ R ¹⁰ means and

R ¹ , R ² , R ³ , R ⁴ , X, m and n have the meaning given in claim 1.

4. Heterocyclically substituted benzamides of the formula I according to claim 1, wherein

R ^{5 means} -CO-OR ⁸ and

R ¹ , R ² , R ³ , R ⁴ , X, m and n have the meaning given in claim 1.

5. Heterocyclically substituted benzamides of the formula I according to claim 1 for use in combating diseases.

6. Use of heterocyclically substituted benzamides of the formula I according to claim 1 for the production of medicaments which are used as inhibitors of cysteine proteases.

7. Use of heterocyclically substituted benzamides of the formula I according to claim 1 for the manufacture of medicaments for the treatment of diseases in which increased calpain activities occur.

8. Use of the heterocyclically substituted benzamides of the formula I according to claim 1 for the manufacture of medicaments for the treatment of neurodegenerative diseases and neuronal damage.

9. Use of the heterocyclically substituted benzamides of the formula I according to claim 1 for the manufacture of medicaments for the treatment of diseases and neuronal damage which are triggered by ischemia, trauma or mass bleeding.

10. Use of the heterocyclically substituted benzamides of the formula I according to claim 1 for the manufacture of medicaments for the treatment of stroke and craniocerebral trauma.

5 11. Use of the heterocyclically substituted benzamides of the formula I according to claim 1 for the manufacture of medicaments for the treatment of Alzheimer's disease and Huntington's disease.

10 12. Use of the heterocyclically substituted benzamides of the formula I according to claim 1 for the manufacture of medicaments for the treatment of epilepsy.

13. Use of the heterocyclically substituted benzamides of formula I according to claim 1 for the manufacture of medicaments for the treatment of heart damage after cardiac ischemia, kidney damage after renal ischemia, skeletal muscle damage, muscular dystrophy, damage caused by proliferation of smooth muscle cells, 20 coronary vasospasm, cerebral vasospasm, cataracts of the eyes and restenosis of the bloodstream after angioplasty.

14. Use of the heterocyclically substituted benzamides of the formula I according to claim 1 for the production of medicaments

25 for the treatment of tumors and their metastasis.

15. Use of the heterocyclically substituted benzamides ket-top zamido aldehydes of the formula I according to claim 1 for the manufacture of medicaments for the treatment of diseases

30 who experience increased interleukin-1 levels.

16. Use of the heterocyclically substituted benzamides of the formula I according to claim 1 for the manufacture of medicaments for the treatment of immunological diseases such as inflammation

35 genes and rheumatic diseases.

17. A pharmaceutical preparation containing a heterocyclically substituted benzamide of the formula I according to claim 1.

40

45