MXPA00010149A - Substituted benzamides, their production and their use as cysteine protease inhibitors - Google Patents

Abstract

The invention relates to benzamides of general formula (I) and their tautomeric forms, as well as to possible enantiomeric and diastereomeric forms, to their E and Z forms and to possible physiologically compatible salts, where the variables R1, R2, R3, A and B have the meanings given in claim 1. The invention also relates to their use as inhibitors of cysteine proteases.

Description

SUBSTITUTE BENZAMIDES, NOVEDOSAS, ITS PREPARATION AND USE The present invention relates to novel benzamides which are inhibitors of enzymes, especially cysteine proteases such as calpain (= calcium-dependent cistern proteases) and their isoenzymes and cathepsins, for example B and L). Calpains are intracellular proteolytic enzymes from the group of cysteine proteases and are found in multiple cells. Calpains are activated by an increase in calcium concentration, making a difference 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 concentrations of -molar calcium ions (P. Johnson, Int. J. Biochem., 1990, 22 (8), 811-22). Other calpain isoenzymes have now also been postulated (K. Suzuki et al., Biol. Chem. Hoppe-Seyler, 1995, 367 (9), 523-9). It is suspected that calpains play an important role in different physiological processes. These include cleavages or dissociations 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 platelet activation, metabolism of neuropétides, proteins in mitosis and others that 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.

High concentrations of calpain have been measured in different pathophysiological processes, for example: heart ischemia (for example, myocardial infarction), or kidney or central nervous system (for example, cerebrovascular accident), inflammations, muscular dystrophies, cataracts of the eyes, injuries of the central nervous system (for example, trauma), alzheimer's disease, etc. (see KK Wang, in the above). It is suspected that there is a relationship between these conditions and high and persistent concentrations of intracellular calcium. This gives rise to overactivation of calcium-dependent processes, which are then no longer subject to physiological control. Therefore, over-activation of calpams can also induce pathophysiological processes. Therefore, it has been postulated that inhibitors of calpain enzymes may be useful to treat these abnormalities. Various investigations have confirmed this fact. Thus, Seung-Chyul Hong et al., Stro e 1994, 25 (3), 663-9 and RT Bartus et al., Neurological Res. 1995, 17, 249-58 have shown a neuroprotective effect of calpain inhibitors. in neurodegenerative diseases acute or ischemia such as those that occur after stroke. Likewise, calpain inhibitors improve the recovery of memory deficits and neuromotor disorders that occur after experimental brain trauma (KE Saatman et al., Proc.Nat.Accid.Sci.USA, 1996, 93, 3428-3433). C.L. Edelstein et al., Proc. Nati Acad. Sci. USA, 1995, 92, 7662-6, which found a protective effect of calpain inhibitors in kidneys damaged by hypoxia, Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59 (1), 40-8, could have beneficial effects of calpain inhibitors after cardiac damage caused by ischemia or reperfusion. In view of the fact that the release of the β-AP4 protein is inhibited by calpain inhibitors, a potential therapeutic use for Alzheimer's disease has been proposed (J. Higaki et al., Neuron, 1995, 14, 651-59). The release of interleukin-la is likewise inhibited by calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6 (6), 597-601). In addition, it has been found that calpain inhibitors have cytotoxic effects on tumor cells (E. Shiba et al., 20th Meeting Int. Ass. Breast Cancer Res.,? Endai Jp, 1994, 25-28 September, Intl. J. Oncol. 5 (Suppl.), 1994, 381). In addition, the possible uses of calpam inhibitors are detailed in K. K. Wang, Trends in pharmacol. Sci. 1994, 15, 412-8.

Calpain inhibitors have already been described in the literature. However, these are mainly peptide inhibitors. Many known reversible inhibitors of cysteine proteases such as calpain are, however, peptide aldehydes, in particular peptide and tripeptide aldehydes such as, for example, Z-Val-Phe-H (MDL 28170) (S. Medhi, Trends in Biol. Sci. 1991, 16, 150-3). Under physiological conditions, the aldehyde peptides have the disadvantage, due to their high reactivity, that they are usually unstable, can be rapidly metabolized and are prone to non-specific reactions that can cause toxic effects (JA Fehrentz and B. Castro, Synthesis 1983, 676- 78). Peptide ketone derivatives in the same way are inhibitors of cysteine proteases, in particular calpams. Thus, for example, ketone derivatives where the keto group is activated by a group that attracts electrons such as CF3 are known to be inhibitors of serine proteases. In the case of cysteine proteases, derivatives with ketones activated by CF3 or similar groups have little or no activity (M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13). To date only ketone derivatives in which, on the one hand, the leaving groups in position a cause irreversible inhibition and, on the other hand, the keto group is activated by acid derivative Carboxylic acids have been found to be effective inhibitors of calpain (see M. R. Angelastro et al., see above, WO 92/11850, WO 92,12140, WO 94/00095 and WO 95/00535). However, many of these inhibitors are obtained from peptides (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 in the above M.R. Angelastro et al.). Ketone derivatives having a hetero group at position a have also been described as calpain inhibitors. Thus, the sulfur derivatives (see EP 603873) and oxygen derivatives (see WO 95/15749 and RE Dolle et al., Med. Chem. 1995, 38, 220-22) in which these heteroatoms are in the position A for the ketone group are known. Ketones having an amino or amido group in the a-position thereof are known, but usually in structures obtained from peptides. Thus, EP 603873 has mentioned α-amino radicals carrying a heterocycle, the α-amides in the same way have been described several times: D. L. Flynn et al., Am. Chem. Soc. 1997, 119, 4874-4881; S. Natarajan et al., J. Enzym. Inhib. 1988, 2, 91-97; J. D. Godfrey et al., J. Org. Chem. 1986, 51, 3073-3075; GB 2170200; EP 159156; EP 132304; US 4470973 and JP 59033260. Most of the derivatives described herein are substituted on the amide residue by other amino acid derivatives. However, the amide: in the same way it has been described by D. L. Flynn et al. (see above). On the other hand, the derivatives in which the benzamide group has a substituent have not been mentioned. In addition, most of the compounds have been postulated as inhibitors of the angiotensin-converting enzyme. An analogous sulfonamide but once again without substitution in the benza ida fragment has been described in RF Meyer et al., J. Med. Chem. 1982, 25, 996-996 [sic], also as an angiotensin-converting enzyme inhibitor. . JP 06035142 (CA 121, 267626) has described benzamide derivatives analogous to the general structure I as photographic material, although hydantoin heterocycles or other groups sensitive to oxidation reactions are included in R1. The novel compounds of the formula I in which the substitutions in the benzamide and in the position a for the keto group perform important functions, with a group Amido or sulfonamido being in position a, have not been described above and therefore are novel.

In various treatments, such as [lacuna] stroke, the active ingredients are administered intravenously, for example, as a solution for transfusion. To do this it is necessary to have substances available, in this case calpain inhibitors having adequate solubility in water so that a solution for transfusion can be prepared. Many of the described calpain inhibitors have, however, the disadvantage that they are only slightly or not soluble in water and thus are unsuitable for intravenous administration. Active ingredients of this type can only be administered with auxiliary substances proposed to confer water solubility (see R. T. Bartus et al., J. Cereb Blood Flow Metab 1994, 14, 537-544). These auxiliary substances, for example, polyethylene glycol, usually have side effects, however, or are even incompatible. A non-peptide calpain inhibitor that is soluble in water without auxiliary substances in this way would be a great advantage. These inhibitors have been poorly described in the foregoing and therefore would show particular advantages. The benzamide derivatives are described in the present invention. These compounds are novel and some derivatives surprisingly show the possibility of obtaining potent non-peptide inhibitors of cysteine proteases, such as, for example, calpain, incorporating rigid structural fragments. In addition, all the present compounds of the general formula I have at least one aliphatic amino radical and can thus bind [sic] salts with acids. This causes better solubility in water and in this way the compounds show the profile necessary for intravenous administration as is necessary, for example, for stroke treatment. The present invention relates to the substituted benzamides of the formula I. and its tautomeric forms, the possible enanitomeric and diastereomeric forms, the E and Z forms, and possible physiologically tolerated salts, in which the variables have the following meanings: R Ci-Cß alkyl, branched or unbranched, where one of the C atoms in this chain may be substituted by a phenyl ring, cyclohexyl ring, mdolyl ring and an SCH3 group, and the phenyl ring in turn is substituted by a maximum of two radicals R, where R is hydrogen, C1-C4 alkyl, branched or unbranched, -O-C1-C4 alkyl, OH, Cl, F, Br, I, CF3, N0, NH2, CN, COON, COO-C1-C4 alkyl, NHCO-alkyl C1-C4, and it can be NR5CO-R6 NHR5S02-R6, and is chlorine, bromine, fluorine, Ci-Cß alkyl, NHCO-C1-C4 alkyl, NHS02-C1-C4 alkyl, N02, -O-Ci-C4 alkyl, CN, COOH, CONH2, COO C1 alkyl -C4, S02-alkyl of C1-C4, S02Ph, S02NH-C1-C4 alkyl, iodine, S02NH2 and NH2, and it can be aromatic rings and heteroaromatic rings such as naphthyl, quinolmyl, quinoxalyl, benzimidazolyl, benzothienyl, quinazolyl, phenyl, thienyl, imidazolyl, pyridyl, pyrimidyl and pyridazyl, it also being possible for the rings to be substituted by R and up to two radicals R, and Ss ^ Zajíi it's a link, - < CH_) m-, - < CH2) p-0- < CH2) o-, - (CHj) 0-S- (CH2) n-, - (CH2) O-S0- (CH2) B- »- (CH2) O-S02- (CH2)" -, -CH = CB-, -CmC-, -CO-CH = CH-, - (CH2) or -CO- (CH2) B-, - (CH2) m-NHC0- (CH2) or-, - < CH2) m-CONH- < CH2) 0-, - < CH2) B-NHS02- (CH2) or-, -NH-CO-CH-CH-, - < CH2) m-S02NH- (CH2) or-, A-B together as well: R is hydrogen and C1-C4 alkyl, and R is hydrogen, phenyl, naphthyl, Ci-Cß alkyl, linear or branched, it being possible for a C atom in the chain to be substituted by a phenyl ring which may also be substituted by one or two radicals R, and may be hydrogen, branched or unsubstituted C1-C4 alkyl branched, -O-C1-C4 alkyl, OH, Cl, F, Br, I, CF3, N02, NH2, CN, COOH, COO-C1-C4 alkyl, NHCO-C1-C4 alkyl, phenyl, NHCO phenyl, -NHS02-C1-C4 alkyl, -NHS02-phenyl, -S02-C1-C4 alkyl, pyridine [sic] and S02-phenyl.

R 9 is hydrogen, -CHR 14- (CH 2) p-R 12 where R 12 is pyrrolidine [sic], morpholine [sic], piperidine [sic], hexahydroazepma [sic], homopiperazine [sic] and R [lacuna] C 1 -C 6 alkyl, branched or unbranched, and which may also bear a phenyl ring which in turn is substituted by a maximum of two R radicals, where R is hydrogen, C 1 -C 4 alkyl, branched or unbranched, -0-alkyl of C1-C4, OH, Cl, F, Br, I, CF3, N02, NH2, CN, COOH, COO-C1-C4 alkyl, NHCO-C1- alkyl C4, -NHS02-C1-C4 alkyl and -S02- C1-C4 alkyl; Y R 13 is hydrogen and Ci-Cg alkyl, branched or unbranched, and n, p is, independent of each other, a number 0, 1 or 2, and m, or is, independent of each other, a number 0, 1, 2, 3 or 4, and Preferred compounds of the general formula I are those in which: A is phenyl and naphthyl, each of which may be substituted by R, and B is -S02NH-, -CH = CH-, a bond and -C = C- and propyl, butyl and benzyl, R2 is NH-S02-R6 and NH-CO-R6 and is hydrogen and COOH, and is C 1 -C 4 alkyl, branched or unbranched, phenyl, and is hydrogen, - (CH2) -R 12, where R 12 is pyrrolidine, morpholine, piperidine, .a-afc »a & a .J and C-Cβ alkyl, branched or unbranched, and R can be C1-C4 alkyl, branched or unbranched.

Particularly preferred compounds of general formula I are those in which: 9 is phenyl which may also be substituted by R, and is -CH = CH-, and radical B is in the ortho position for the benzamide of general formula I, and R butyl and benzyl, R2 is NH-S02-R6, and it's hydrogen R is C 1 -C 4 alkyl, branched and unbranched, [sic] and phenyl, and R9 is hydrogen, - (CH2) -R12, where R12 is pyrrolidine, morpholine, piperidine, -NR R and and R 1 Ci-Cβ alkyl, branched or unbranched, and R C 1 -C 4 alkyl, branched or unbranched, 14 R can be hydrogen, methyl, ethyl, The compounds of the formula I can be used as racemates, as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are required, these may be obtained, for example, by carrying out a resolution of traditional racemates with the compounds of the formula I or their intermediates using a suitable base or optically active acid. On the other hand, enantiomeric compounds can likewise be prepared using commercially available compounds, for example, optically active amino acids such as phenylalanine, tryptophan and tyrosine. The invention also relates to compounds that are mesomers or tautomers of the compounds of the formula I, for example, those in which the keto group in the formula I is in the form of an enol tautomer. The invention further relates to the physiologically tolerated salts of the compounds I that can be obtained by reacting the compounds I with a suitable acid or base. Suitable acids and bases are iaé & á - mentioned, for example, in Forstschritte der Arzneimittelforschung, 1966, Birkhauser Verlag, vol. 10, page 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, etc., and sodium hydroxide, lithium hydroxide, hydroxide. potassium and tris. The novel compounds of the general formula I can be prepared in different forms as described below (see scheme 1). A benzoic acid II, which, when appropriate, [lacuna] simply forms analogous esters by hydrolysis with acids such as hydrochloric acid, or bases such as lithium hydroxide or sodium hydroxide, in aqueous solutions or water / solvent mixtures, such as Water / alcohols or water / tetrahydrofuran, at room temperature or elevated temperature, up to the boiling point of the solvent, are reacted with suitable amino alcohols III to obtain the IV benzamides. This comprises the use of traditional peptide coupling methods which are detailed in CR [sic] Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972 et seq., Or in Houben-Weyl, Methoden der organischen Chemie, 4th edition, E5, chapter V. The use of "activated" acid derivatives of II is preferred, the acid group being COOH converted to a COL group. L is a leaving group such as, for example, Cl, imidazole and N-hydroxybenzotriazole. This activated acid is subsequently reacted with amines to obtain the IV amides. The reaction is carried out in anhydrous inert solvents such as methylene chloride, tetrahydrofuran and dimethylformamide at temperatures from -20 to + 40 ° C. The amino alcohols III are prepared from alcohols VII analogs (for the method of general synthesis, see J. C. Barrish et al., J. Med. Chem. 1994, 37, 1758-1068). This consists in reacting VII, analogous to the previous ones, with acids or sulfonic acids to obtain the corresponding amides or sulfonamides VIII. The protective group Z, which is usually BOC or Cbz, is then removed. This includes the use of procedures traditional, for example, with BOC acids such as trifluoroacetic acid, or hydrochloric acid, in solvents such as methylene chloride or mixtures of water and alcohols or tetrahydrofuran. The alcohol IV derivatives can be oxidized to the novel aldehyde I derivatives. It is possible to use for this different traditional oxidation reactions (see C. R. Larock, Comprehensive [sic] Organic Transformations, VCH Publisher, 1989, page 604 et seq). Such as, for example, the Swern and analogous Swern oxidations (T. T. 5 Tidwell, Synthesis, 1990, 857-70), sodium hypochloride [sic] / TEMPO (S. L. Harbenson et al., see above) or Dess-Martin (J. Org. Chem. 1983, 48, 4155). These are preferably carried out in inert aprotic solvents such as dimethylformamide, tetrahydrofuran or methylene chloride with oxidizing agents such as DMSO / pyridine x SO3, DMSO / oxalyl chloride or DMSO / DCC or EDC at temperatures from -50 to +25 ° C, depending on of the method (see previous literature).

Scheme 1 Otherwise, it is possible to react an amino alcohol III with a benzoic acid V in analogy to the linkage of II and III to obtain the benzamide derivative VI. In this case, R 'is a functional group that then allows conversion to the AB radicals, according to the invention (see below). Thus, R 'in VI can be, for example, a nitro group which can subsequently be reduced with catalysts in the conventional manner, for example, with palladium / carbon in water-soluble solvents such as alcohols, with hydrogen to obtain an analogous aniline (R '= NH2). This amino group can then be converted to the amides or sulfonamides. This comprises reacting the aniline with carboxylic acid derivatives or sulfonic acid in analogy to the linkage (II + III). Other radicals and the transformation thereof can be used respectively and be carried out in analogy with the mentioned methods to prepare the AB-substituted benzoic acid derivatives. In the cases where R in IV is a carboxylic ester, it can be hydrolyzed with bases and acids, for example, lithium hydroxide, sodium hydroxide and hydrochloric acid, in aqueous systems or water / solvent mixtures, such as water / alcohols and water / tetrahydrofuran, to the carboxylic acid, at room temperature or elevated temperature (up to the boiling point of the solvent). The oxidation to I is then carried out as already described.

Scheme 2 Vil VIII III The synthesis of carboxylic esters II has already been described in some cases, or can be prepared by traditional chemical methods. The compounds in which B is a bond are prepared by traditional aromatic association, for example, Suzuki's association with boric acid derivatives and halides with palladium catalysts, or copper-catalyzed association of the aromatic halides. Alkyl bridge-forming radicals (B = - (CH2) m-) can be prepared by reducing analogous ketones or by organolithium alkylation, for example, ortho-phenyloxazolidines [sic], or other organometallic compounds (see, IM Dordor et al. , J. Chem. Soc. Perkin Trans. I, 1984, 1247-52). The ether bridge-forming derivatives are prepared by alkylation of the corresponding alcohols or phenols with halides. Sulfoxides and sulfones they can be obtained by oxidation of the corresponding thioethers. The compounds forming alkene and alkyne bridges are prepared, for example, by the reaction of Heck from aromatic halides and the appropriate alkenes and alkynes (see I. Sakamoto et al., CH Pharm. Bull., 1986, 34, 2754-59). Chalcones are produced by condensing acetophenones with aldehydes and can, where appropriate, be converted to the analogous alkyl derivatives by hydrogenation. The amides and sulfonamides are prepared from the amines and the acid derivatives in analogy with the methods described above. The benzamide derivatives I of the present invention are inhibitors of cysteine proteases, especially cysteine proteases such as calpains I and II and cathepsin B and L. The inhibitory effect of benzamides I has been determined using enzymatic assays known from the literature, determining as criteria of effect a concentration of the inhibitor to which 50% of the enzymatic activity is inhibited (= IC50). Amides I were measured in this way for its inhibitory effect on calpain I, calpain II and cathepsin B.

Cathepsin B assay The inhibition of catpesin B was determined in a manner analogous to a method of S. Hasnain et al., J. Biol.

Chem. 1993, 268, 235-40. 2 μl of a solution of the inhibitory ingredient, prepared from the inhibitor and DMSO (final concentrations: 100 μM to 0.01 μM) are added up to 88 μl of cathepsin B (human liver cathepsin B (Calbiochem), diluted to 5 units in 500 μM buffer). This mixture is preincubated at room temperature (25 ° C) for 60 minutes and then the reaction is started by the addition of 10 μl of 10 μl Z-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is monitored at 405 nM in a microtiter plate reader for 30 minutes. The IC 50 are then determined from the maximum gradients.

Calpain I and II Assay The tests for the inhibitory properties of calpain inhibitors are carried out in buffer using 50 mM tris HCl, pH 7.5; 0.1 M NaCl; dithiothreitol [sic] 1 mM; 0.11 mM CaCl2, the fluorogenic calpain substrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachem / Switzerland) being used. The human μ-calpain is isolated from the erythrocytes and, after several chromatographic steps (DEAE-Sepharose, phenyl-sepharose, Superdex 200 and Blue Sepharose), the enzyme having a purity of > 95%, was evaluated according to SDS-PAGE, Western blot analysis and n-terminal sequencing was obtained. Fluorescence of the product of dissociation 7- amino-4-methylcoumarin (AMC) was monitored in a Spex-Fluorolog fluorometer at? ex = 380 nm and? em = 460 nm. In a measurement interval of 60 minutes, the dissociation of the substrate is linear and the autocatalitic activity of calpain is low, if the experiments are carried out at temperatures of 12 ° C. The inhibitors and the calpain substrate are added to the experimental lot as solutions in DMSO, where the DMSO should not exceed 2% in the final concentration. In a test mixture, 10 μl of the substrate (250 μM final) and then 10 μl of μ-calpain (2 μg / ml final, ie 18 nM) are added to a 1 ml cell containing buffer. Calpain-mediated dissociation of the substrate is measured for 15-20 minutes. 10 μl of the inhibitor (50-100 μM solution in DMSO) are then added and the addition of the dissociation is inhibited for another 40 min. The Kx values are determined according to the traditional equation for reversible inhibition: Ki [sic] = 1 / (vo / vi) [sic] - 1; wherein I = inhibitor concentration, vo [sic] = initial velocity before the addition of the inhibitor; vi [sic] = reaction speed at equilibrium. The speed is calculated from v = AMC release / time, that is, height / time. When testing 3 (2-naphthylsulfonamide) -N- (3- (S) -4-phenyl-1- phenylsulfonamidobutan-2-on-3-yl) benzamide [sic] (Example 1, an inhibition of more than 50% calpam I was found at a concentration of 1 μM, and thus, Z for Example 1 is <1 μM Calpain is an intracellular cysteine protease Calpain inhibitors must cross the cell membrane to prevent the breakdown of intracellular proteins by calpain Some known calpain inhibitors, such as, for example, E 64 and leupeptin, only cross more cell membranes with difficulty and, therefore, show, although they are good inhibitors of calpain, only a deficient action in the cells.The objective is to find compounds more able to cross the membrane.They use human platelets to demonstrate the ability of calpain inhibitors to cross the membrane.

Tyrosine kinase calpain-mediated breakdown pp60src in platelets After activation of platelets, the ppdOsrc tyrosine kinase is split or dissociated by calpain.

This was investigated in detail by Oda et al., In J. Biol.

Chem., 1993, vol 268, 12603-12608. In this context, it was shown that dissociation of pp60src can be prevented by calpeptin, a calpain inhibitor. The effectiveness cellular of our substances was tested after this publication. Fresh human blood treated with citrate was centrifuged at 200 g for 15 minutes. Platelet-rich plasma was combined and diluted 1: 1 with platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KCl, 0.5 mM MgCl2 x 6 H20, 0.24 mM NaH2P04, 12 mM NaHCO3, 5.6 mM glucose, 1 mM EDTA, pH 7.4). After one step of centrifugation and washing with platelet buffer, the platelets were adjusted to 10 cells / ml. The isolation of human platelets was performed at room temperature. In the assay mixture, isolated platelets (2 x 10) were preincubated at 37 ° C with different concentrations of the inhibitors (dissolved in DMSO) for 5 minutes. The platelets were then activated with 1 μM A23187 ionophore and 5 mM CaCl2. After incubation for 5 minutes, the platelets were centrifuged briefly at 13,000 rpm and the package was taken 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 μg / ml pepstatin, 10% glycerol and 1% SDS). The proteins were separated in a 12% concentration gel and pp60src and their 52 kDa and 47 kDa dissociation products were identified by Western blot analysis. The polyclonal rabbit anti-Cys-src antibody (pp60c rc) used was purchased from the company Bio ol Femchernikalien (Hamburg). This antibody ZJfS. primary was detected using a secondary antibody coupled to goat HRP (Boehringer Mannheim, FRG). The Western blot analysis was performed according to the known methods. The quantification of the dissociation of pp60src was performed by densitometry, the controls used being platelets not activated (control 1: without dissociation) and platelets treated with ionophore and calcium (control 2: corresponds to 100% dissociation). The ED50 value corresponds to the concentration of the inhibitor at which the intensity of the color reaction is reduced by 50%.

Cell death induced by glutamate in cortical neurons The test was performed as in Choi D. W., Mauliccin-Gedde M.A. and Kriegstein A.R. "Glutamate neurotoxicity in cortical cell culture". J. Neurosci. 1989, 7, 357-368. The cortex halves were dissected from 15 day old mouse embryos, and the individual cells were obtained by enzymatic means (trypsin). These cells (glial and cortical neurons) are inoculated into 24-well plates. After three days (plates coated with laminin) or seven days (plates coated with ornithine), the mitosis treatment is performed using FDU (5-fluoro-2-deoxyuridines [sic]). 15 days after cell preparation, cell death is induced by the addition of glutamate (15 minutes). After the separation of the glutamate, the calpain inhibitors are added. 24 hours later, cell damage is determined by determining the lactate dehydrogenase (LDH) in the cell culture supernatant. It is postulated that calpain also plays an important role in programmed cell death (MKT 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 induced with calcium in the presence of calcium ionophore in a line of human cells. Calpain inhibitors must pass into the cell and inhibit calpain there to prevent induced cell death.

Calcium-mediated cell death in NT2 cells It is possible to induce cell death in the human NT2 cell line by means of calcium in the presence of the A23187 ionophore. 10 cells / well were plated in microtiter plates 20 hours before the experiment. After this period, the cells were incubated with different concentrations of the inhibitors in the presence of 2.5 μM ionophore and 5 mM calcium. 0.05 ml of XTT (cell proliferation enzyme II, Boehringer Mannheim) was added to the reaction batch after 5 hours. The determination of optical density approximately 17 hours later, according to the manufacturer's instructions, on the Easy Reader EAR 400 of the company SLT. The optical density at which half of the cells were dead is calculated from the two controls with cells without inhibitors, which were incubated in the absence and presence of the ionophore. In certain neurological diseases or psychological disorders, the activity of glutamate increases, which gives rise to states of over stimulation or toxic effects in the central nervous system (CNS). Glutamate mediates its effects through different receptors. Two of these receptors are classified by specific agonists as NMDA receptor and AMPA receptor. Substances that weaken these glutamate-mediated effects in this way can be used for the treatment of these diseases, in particular for therapeutic administration against neurodegenerative diseases such as Huntmgton's disease and Parkinson's disease, neurotoxic disorders after hypoxia, anoxia, ischemia. and after injuries, such as after stroke and trauma, or otherwise as antiepileptics (see Arzneim, Forschung 1990, 40, 511-514, TIPS, 1990, 11, 334-338, Drugs of the Future 1989, 14, 1059-1071).

Protection against over-stimulation of the brain by excitatory amino acids (antagonism of NMDA or AMPA in mice) As a result of intracerebral administration of excitatory amino acids (EAA), such over mass stimulation is induced so that a short time this gives rise to spasms and the death of animals (mice). These symptoms can be inhibited by systemic, for example, intraperitoneal administration of the centrally active compounds (EAA antagonists). In view of the fact that the excessive activation of the EAA receptors of the central nervous system play an important role in the pathogenesis of different neurological disorders, a conclusion can be drawn from the antagonism of EAA demonstrated in vivo on a possible therapeutic utility of the substances against disorders of the brain. SNC of this type. As a measure of the efficacy of the substances, an ED5 value was determined in which 50% of the animals showed no symptoms as a result of a fixed dose of NMDA or AMPA as a result of the i.p. previous of the normal substance. The benzamide derivatives I are inhibitors of cysteine derivatives [sic] such as calpain I and II and cathepsin B and L and can thus be used for the control of diseases that are associated with increased activity Enzymatic Calpain enzymes or cathepsin enzymes. The amides I present can therefore be used for the treatment of neurodegenerative processes that occur after ischemia, trauma, hemorrhages, subarachnoids and stroke, and neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease, Huntington's disease and epilepsy. and also for the treatment of damage to the heart after cardiac ischemia, damage and reperfusion after vascular occlusion, damage to the kidneys after renal ischemia, skeletal muscle damage, muscular dystrophy, damage that occurs due to the proliferation of the cells of the heart. smooth muscle, coronary vasospasm, cerebral vasospasm, cataracts of the eyes, restenosis of blood flow after angioplasty. In addition, amides I may be useful in the chemotherapy of tumors and their metastasis and for the treatment of diseases in which a higher concentration of interleukin-1 occurs, such as in inflammations and rheumatic disorders. The pharmaceutical preparations according to the invention contain a therapeutically effective amount of the compounds I in addition to the traditional pharmaceutical auxiliaries. The active ingredients may be present in the normal concentrations for local external use, for example in powders, ointments or rubbers.

As a general rule, the active ingredients are present in an amount from 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight. For internal use, the preparations are administered in single doses. 0.1 to 100 mg is given per kg of body weight in a single dose. The preparation can be administered in one or more doses per day, depending on the nature and severity of the conditions. The pharmaceutical preparations according to the invention contain, in addition to the active ingredient, the customary excipients and diluents suitable for the mode of administration. For external, local use, pharmaceutical auxiliaries such as ethanol, isopropanol, ethoxylated castor oil, hydrogenated castor oil, ethoxylate, polyacrylic acid, polyethylene glycol, polyethylene glycol [sic], stearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum and fat of wool can be used. For internal administration, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable. Antioxidants such as tocopherol and butylated hydroxyanisole as well as butylated hydroxytoluene, flavor enhancing additives, stabilizers, emulsifiers and lubricants may also be contained. The substances contained in the preparation in addition to active compound and the substances used in the production of the pharmaceutical preparations are toxicologically acceptable and compatible with the respective active compound. The pharmaceutical preparations are produced in a customary manner, for example by mixing the active compound with other customary excipients and diluents. The pharmaceutical preparations can be administered in different forms, for example, orally, parenterally, as intravenously, by transfusion, subcutaneously, intraperitoneally and topically. Thus, forms of preparation such as tablets, emulsions, solutions for transfusion and injection, pastes, ointments, gels, creams, lotions, powders and rubbers are possible.

Examples Example 1 3 (2-naphthylsulfonamido) -N (3- (S) -4-phenyl-1-phenylsulfonamidobutan-2-on-3-yl) benzamide [sic] a) N- (1- n-tro-4-phenylbutan-2-ol-3-yl) carbamate of O-tert-butyl 31.8 g (0.52 mol) of nitromethane and 12.5 ml of diethylamine were dissolved in 125 ml of ethanol. Then, 43.3 g (0.17 mol) of O-tert-butyl N (2- (S) -3-phenylpropion-1-yl-3-yl) carbamate (AW Konradi et al., J. Am. Chem. Soc. 1994, 1316-1323) were added in portions. The reaction mixture was stirred at room temperature for 16 hours. The mixture was subsequently concentrated in vacuum. The residue was dissolved in ethyl acetate and washed successively with aqueous solutions of citric acid and sodium bicarbonate at 5% concentration. The organic phase was dried and concentrated in vacuo, giving rise to 51.4 g (95%) of the product. b) N (2- (R, S) -3- (S) -l-ammon? o-4-phenylbutan-2-ol-3-? l) -O-tert-butylcarbamate acetate [sic] 58.9 g ( 0.19 mol) of intermediate 1 were dissolved in 750 ml of tetrahydrofuran / methanol (2/1) and, after the addition of 58 g of palladium / barium sulfate (5%) and 10 ml of glacial acetic acid, was reduced with hydrogen. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was treated with ether, whereupon the product crystallized as acetate. c) N- (2- (R, S) -2- (S) -1-phenylsulfonamido-4-phenylbutan-2-ol-3-yl) carbamate 0- (tert-butyl) [sic] 2.5 g (7.3 mmol) of intermediate 1 b were dissolved in 25 ml of pyridine. Then, at 0 ° C, 1.36 g (7.7 mmol) of benzenesulfonyl chloride, dissolved in 5 ml of anhydrous tetrahydrofuran, were rapidly added dropwise. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was treated with water, whereupon the product crystallized slowly. 2.6 g (89%) of the product were obtained. d) N (2- (R, S) -3- (S) -l-amino-4-phenylbutan-2-ol-1-yl) benzenesulfonamine [sic] 2.2 g (5.1 mmol) of the intermediate were dissolved in 50 ml of methylene chloride, and 50 ml of saturated ethereal chloride solution were added. The mixture was stirred at room temperature for one hour. The reaction mixture was then concentrated in vacuo, and the resulting residue was treated with ether, whereupon the product slowly separated as hydrochloride. Yield 1.8 g (97%). e) ethyl 3- (2-naphthl-sulfonamido) benzoate 34.3 g (0.15 mol) of 2-naphthalenesulfonyl chloride, dissolved in 250 ml of tetrahydrofuran, were added dropwise to 25 g (0.15 mol) of 3 - ethyl aminobenzoate and 63 ml (0.45 mol) of triethylamine in 400 ml of tetrahydrofuran at 0 ° C. The mixture was then heated to reflux for one hour. The organic solvent was removed in vacuo, and the residue was separated between ethyl acetate and water. The ethyl acetate phase was dried and concentrated in vacuo. 55 g (100%) of the product were obtained f) 3- (2-naphthylsulfonamido) benzoic acid 55 g (0.15 mol) of intermediate 7a were dissolved in 400 ml of tetrahydrofuran, and 400 ml of 4M sodium hydroxide solution was added. The mixture was stirred at 60 ° C for 1.5 hours. The organic solvent was removed in vacuo. The remaining aqueous phase was stirred in dilute hydrochloric acid. The resulting precipitate was dissolved in ethyl acetate, washed with water, dried and concentrated in vacuo. Then the residue was treated with methylene chloride. Subsequently, 37.3 g (75%) of the product were obtained. g) 3- (2-naphthl-sulfonamido) -N (2- (R, S) -3- (S) -4-phenyl-1-phenylsulfonam? dobutan-2-ol-3-yl) benzamide [sic] 0.87 g (2.7 mmol) of intermediate lf and 0.36 g (2.7 mmol) of 1-hydroxybenzotriazole were dissolved in 5 ml of anhydrous dimethyl sulfoxide. Then another solution of 0.95 g (2.7 mmol) of the intermediate Id and 0.94 g (9.3 mmol) of triethylamine in 5 ml of anhydrous dimethyl sulfoxide was prepared and added to the first solution 0.56 g (2.9 mmol) of N '- (3 hydrochloride. - dimethylaminopropyl) -N-ethylcarbodiimide was then added [sic], and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then mixed with approximately 100 ml of an aqueous solution of sodium chloride / sodium bicarbonate, whereby the product could be seen. Yield: 0.54 g (88%). h) 3- (2-naphthylsulfonamido) -N (3 (S) -4-phenyl-1-phenylsulfonamidobutan-2-on-3-yl) benzamide [sic] 0.2 g (0.32 mmol) of intermediate lg and 0.16 g (1.6 mmol) of triethylamine were dissolved in 5 ml of anhydrous dimethylsulfoxide. Then, at room temperature, 0.2 g (1.3 mmol) of the pyridine / sulfur trioxide complex were added and the mixture was stirred for 16 hours. The mixture of The reaction was poured into 50 ml of an aqueous solution of sodium chloride / sodium bicarbonate, whereupon the product was separated. Yield 0.16 g (80%). XH NMR (D6-DMSO): d = 2.8 (1H), 3.1 (1H), 3.8 (1H), 4.0 (1H), 4.6 (1H), 7.8-8.2 (21H), 8.4 (1H) 8.8 (1H) and 10.6 (broad) ppm.

EXAMPLE 2 N (3 (S) - (4-Phenol-1-phenylsulfonamidobutan-2-on-3-ol) -2- (E-2 (4-pyridyl) -1-ethenyl) benzamide [sic] a) ethyl Ethyl-2- (E-2 (4-pyridyl) -l-ethenyl) benzoate 50 g (0.22 mmol) of ethyl 2-bromobenzoate, 30 g (0.29 mol) of 4-vinylpyridine and 75 ml (054 mol) of triethylamine were dissolved in 750 ml of dimethylformamide. Then, 0.36 g of palladium (II) acetate, 0.96 g of tri- (o-tolyl) phosphine and 1 ml of water were added, and the mixture was refluxed for three hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo. The residue was recrystallized [lacuna] cyclohexane / petroleum ether, yielding 45.3 g (83%) of the product. b) 2- (E-2 (4-pipdyl) -1-ethenyl) benzoic acid [sic] 45 g (0.18 mol) of intermediate 2A were dissolved in 200 ml of tetrahydrofuran and, after 400 ml of tetrahydrofuran had been added. 4M sodium hydroxide, the mixture was refluxed for 4 hours. After cooling, the mixture was diluted with 600 ml of water and neutralized with acetic acid, whereupon the product crystallized. Yield 38.2 g (95%). c) N (2 (R, S) (3 (S) - (4-phenyl-1-phenylsulfonam? dobutan-2-ol-3-ol) -2- (E-2 (4-pyridyl) - 1-ethenyl) benzamide [sic] 0.75 g (2.1 mmol) of the intermediates [sic] Id and 0.47 g (2.1 mmol) of intermediate 2b were reacted in the same way as in the lg method, giving rise to 0.97 g (87 %) of the product. d) N (3 (S) - (4-phenyl-1-phenylsulfonamidobutan-2-on-3-yl) -2- (E-2- (4-pyridyl) -l-ethenyl) benzamide [sic] 0.87 g of the intermediary 2c were oxidized from it as in the lh method, giving rise to 0.78 g of the product. XH NMR (d6-DMS0): d = 2.8 (1H), 3.1 (1H), 3.9 (1H), 4.8 (1H), 7.2-8.2 (18H), 8.6 (2H), and 8.9 (1H) ppm Example 3 N (3 (S) -l-methanesulfonamido-4-phen-lbutan-2-on-3-? L) -2- (E-2 (4-pyridyl) -1-ethene) benzamide [sic] a) N- (2- (R, S) -3 (S) -l-methanesulfonamido-4-phen-lbutan-2-ol-3-yl) -o-tert-butylcarbamate [sic] 2.5 g (7.3 mmol) of intermediate lb were dissolved in 25 ml of pipdma. Then, at 0 ° C, 0.88 g (7.7 mmol) of methanesulfonyl chloride, dissolved in 5 ml of anhydrous tetrahydrofuran, was rapidly added dropwise. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was separated between water and ethyl acetate.

The ethyl acetate phase was then dried and concentrated in vacuo, leaving 2.2 g (82%) of the product. b) N (2 (R, S) -3- (S) -3-amino-4-phenylbutan-2-ol-1-yl) methansulfonamide [sic] 1.85 G (5.1 mmol) of intermediate 3a were dissolved in 50 ml of methylene chloride, and 50 ml of saturated ethereal acid chloride solution were added. The mixture was stirred at room temperature for one hour. The reaction mixture was then concentrated in vacuo, and the resulting residue was treated with eer [sic], whereupon the product slowly separated as hydrochloride. Yield 1.5 g (97%). c) N (2 (R, S) -3 (S) -l-methanesulfonam? do-4-phenylbutan-2-ol-3-yl) -2- (E-2 (4-pyridyl) -1-etem ) benzamide [sic] 0.6 g (2.0 mmol) of the intermediates [sic] 3b and 0.46 g (2.1 mmol) of intermediate 2b were reacted in the same way as for the lg method, yielding 0.62 g (65%) of the product. d) N (3 (S) -l-methanesulfonamido-4-phenylbutan-2-on-3-yl) -2- (E-2- (4-pyridyl) -1-ethenyl) benzamide [sic] 0.5 g of the intermediate 3c were oxidized from the same as for the lh method, obtaining 0.35 g of the product.

XH NMR (d6-DMSO): d = 2.7-3.0 (3H), 3.1-3.4 (2H), 4.1-4.4 (2H), 4.9 (1H), 7.1-8.0 (13H), 8.5 (2H), 9.0 ( 1H) ppm.

Example 4 N (3 (S) -l-Methanesulfonamido-4-phenylbutan-2-on-3-yl) -3- (2-naphthylsulfonamido) benzamide [sic] a) N (2 (R, S) -3 (S) -l-methanesulfonamido-4-phenylbutan-2-ol-3-yl) -3- (2-naphthylsulfonamido) benzamide [sic] 0.8 [lacuna] (2.0 mmol) of the intermediates [sic] 3b and 0.86 g (2.1 mmol) of intermediate lf were reacted in the same manner as for the lg method, giving rise to 1.2 g (81%) of the product. d) N (3 (S) -l-methanesulfonamido-4-phenylbutan-2-on-3-yl) -2- (2-naphthylsulfonamido) benzamide [sic] 1.1 g of intermediate 4a were oxidized in the same manner as for the lh method, giving rise to 0.73 g of the product. XH NMR (de-DMSO): d = 2.8-3.0 (3H), 3.1-3.3 (2H), 3.9- 4. 2 (2H), 4.8 (1H), 7.0-8.2 (17H0) 8.4 (1H), 8.8 (1H) and 10.8 (broad) ppm.

Example 5 N (3 (S) -l-benzamido-4-phenylbutan) -2-on-3-yl) - (2-naphthylsulfonamido) benzamide [sic] a) N- (2- (R, S) -3 (S) -l-benzamidoamido-4-phenylbutan-2-ol-3-yl) -ort-butylcarbamate [sic] 2.5 g (7.3 mmol) ) of intermediate lb were dissolved in 25 ml of pyridine. Then, at 0 ° C, 1.1 g (7.7 mmol) of benzoyl chloride, dissolved in 5 ml of anhydrous tetrahydrofuran, were rapidly added dropwise. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was diluted to 10 times the volume with an aqueous solution of sodium bicarbonate, whereupon the product crystallized. 1.3 g (46%) of the product were obtained. b) N (2 (R, S) -3- (S) -3-amino-4-phenylbutan-2-ol-1-yl) methanesulfonamide [sic] 1.2 g (3.0 mmol) of intermediate 5a were dissolved in 50 ml of methylene chloride, and 20 ml of saturated ethereal acid chloride solution were added. The mixture was stirred at room temperature for one hour. The reaction mixture was then concentrated in vacuo, and the resulting residue was treated with eer [sic], whereupon the product slowly separated as hydrochloride. Yield 1.0 g (99%). c) N (3 (S) -l-benzamido-4-phenylbutan) -2-on-3-yl) -2 (2-naphthylsulfonamido) benzamide [sic] 0.52 g [lacuna] (2.0 mmol) of the intermediates [ sic] 5b and 0.53 g (1.6 mmol) of the intermediate If were reacted in analogous manner with the lg method, giving rise to 0.89 g (92%) of the product. d) N (3 (S) -l-benzamido-4-fenllbutan) -2-on-3-yl) -2 (2-naphthylsulfonamido) benzamide [sic] 0.78 g of intermediate 5c were oxidized from the same as for the lh, giving rise to 0.72 g of the product. * H NMR (de-DMSO): d = 2.8 (1H), 4.3 (2H), 4.7 (1H), 7.0- 8.3 (20H), 8.4 (1H), 8.7-8.9 (2H), ppm.

Example 6 N (3 (S) -4-phenyl-1-benzam? Dobutan-2-on-3-yl) - (2- (E-2 (4-pyridyl) -l-ethene) l) benzamide [sic] ] a) N- (2 (R, S) -3 (S) -4-phenyl-l-benzam? dobutan-2-ol-3-? l) - (2- (E-2 (4-p? r ? d? l) -1-ethenyl) benzamide [sic] 0.4 [lacuna] (1.25 mmol) of the intermediates [sic] 5b and 0.28 g (1.25 mmol) of intermediate 2b were reacted in the same way as for the lg method , giving rise to 0.54 g (88%) of the product. b) N (3 (S) -4-phenyl-1-benzamidobutan-2-on-3-yl) - (2- (E-2- (4-pyridyl) -1-ethenyl) benzamide [sic] 0.48 g of the intermediate 6a was oxidized in analogy with the Ih method, giving rise to 0.42 g of the product MS: m / e = 489 (M +).

The following compounds were prepared in analogy with the previous examples: Example 7 3- (4- (1- (N, N-dimethylamino) -1-ethyl) -phenylsulfonamido) -N (l-phenylsulfonamido-heptan-2-on-3-? L) benzamide XH NMR (d6-DMSO): d = 0.7-1.0 (3H), 1.0-1.8 (12H), 2.9-3.2 (8H), 3.9-4.2 (2H), 4.6 (1H), 7.2-8.0 (14H), ppm.

Example 8 N- (1-phenylsulfonamido-heptan-2-on-3-yl) -3- (4- (1- (piperinidin-1-yl) -1-ethylphen-lsulfonamido) benzamide XH NMR (d6-DMSO): d = 0.8 (3H), 1.1-1.8 (10H), 3.1 (1H), 3.9 (2H), 4.4 (1H), 7.2-8.1 (14H) and 8.7 (1H) ppm.

Example 9 3- (4- (1- (1-methyl-piperazin-1-yl) -1-ethyl) -phenylsulfonamido-N- (1-phenylsulfonamido-heptan-2-on-3-yl) -benzamide XH NMR (d6-DMSO): d = 0.9 (6H), 1.1-1.6 (6H), 2.3-2.8 (11H), 3.1 (1H), 3.9-4.1 (2H), 4.7 (1H) and 7.2-8.0 (14H) ppm.

The following examples can be prepared in the same way as the previous examples: N (3 (S) -4-Phenyl-l-phenylsulfonam? Do-butan-2-on-3-yl) -2- (E-2-phenyl-1-ethene) -benzamide 2 (E-2) (3,4-Dimethoxyphenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulfonamido-butan-2-on-3-yl) benzamide, 2 (E-2 (2-Naft? l) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulfonamido-butan-2-on-3-l) -benzamide 2 (E-2 (4 (N, N-Dimethylaminomethyl)) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulfonamido-butan-2-on-3-yl) -benzamide 2 (E-2 (4 (N, N-Diethylaminomethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulfonamido-butan-2-on-3-yl) -benzamide N (3 (S) -4-Phenyl -l-phenylsulfonamido-butan-2-on-3-yl) -2 (E-2- (4- (pyrrolidin-1-ylmethyl) -phenyl) -1-ethenyl-benzamide 2 (E-2 (4 (P? pepdin-1-ylmethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulfonamido-butan-2-on-3-yl) -benzamide 2 (E-2 (4 ((4-Methylpiperazin-1-yl) methyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulphon-amido-butan-2-on-3-yl) -benzamide 2 (E-2 (4 (N, N-Benzyl-methylaminomethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulfon-am? Do-butan-2-on-3- il) -benzamide 2 (E-2 (4- (4-Ethylpiperazm-l-ylmethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulfon-amido-butan-2-on -3-yl) -benzamide 2 (E-2 (4- (4-Benzl-lperaperazin-1-ylmethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-phenylsulfon- amido-butan-2-on-3-yl) -benzamide N (l-Phenylsulfonamido-heptan-2-on-3-yl) -2 (E-2-phenyl-l-ethenyl) -benzamide 2 (E-2 (3, 4-dimethoxyphenyl) -1-ethenyl) -N (-1-phenylsulfonamido-heptan-2-on-3? -l) -benzamide 2 (E-2 (2-Naphthyl) -1 -etenyl) - (1-phenylsulfonamido-heptan-2-on-3-yl) -benzamide 2 (E-2 (4 (N, N-Dimethylaminomethyl) phenyl) -1-ethenyl) - (1-phenylsulfonamido- heptan-2-on-3-? l) -benzamide 2 (E-2 (4 (N, N-Diethylaminomethyl) phenyl) -1-ethenyl) - (1-phenylsulfonamido-heptan-2-on-3-yl) -benzamide N (l-Femlsulfonamido-heptan-2-on-3-? l) -2 (E-2 (4-pyrrolidin-l-ylmethyl) -phenyl) -1-ethenyl) -benzamide 2 (E- 2 (4 (Pperidin-1-ylmethyl) phenyl) -1-ethenyl) -N (1-phenylsulfonamido-heptan-2-on-3-yl) -benzamide 2 (E-2 (4 ((4-Methylpiperazine -l-? l) methyl) phenyl) -1-ethenyl) - (1-phenylsulfonamido-heptan-2-on-3-? l) -benzamide 2 (E-2 (4 (N, N- Benzyl-methylaminomethyl) phenyl) -1-ethenyl) -N- (1-phenylsulfon-amido-heptan-2-on-3? -l) -benzamide 2 (E-2 (4 (4-Ethylp? Perazin -l-ylmethyl) phenyl) -1-ethenyl) -N- (1-phenylsulfonamido-heptan-2-on-3-yl) -benzamide 2 (E-2 (4 (4-Benzylpiperazin-1-ylmethyl) ) phenyl) -1-ethenyl) -N- (1-phenylsulfonamido-he ptan-2-on-3-yl) -benzamide N (3 (S) -l-Methanesulfonamido-heptan-2-on-3-? l) -2 (E-2-phenyl-l-ethenyl) -benzamide 2 (E-2 (3, 4-dimethoxyphenyl) -1-ethenyl) -N (3 (S) -1-methanesulfonamido-heptan-2-on-3-yl) -benzamide 2 (E-2 (2-Naft? l) -1-ethenyl) -N (3 (S) -1-methanesulfonamido-heptan- 2-on-3-yl) -benzamide 2 (E-2 (4 (N, N-Dimethylaminomethyl) phenyl) -1-ethenyl) -N (3 (S) -1-methanesulfonamido-hepan-2-on-3 -yl) -benzamide 2 (E-2 (4 (N, N-Diethylaminomethyl) phenyl) -1-ethenyl-N (3 (S) -1-methanesulfonamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Methanesulfonamido-heptan-2-on-3-yl) -2 (E-2- (4 (pyrrolidin-1-ylmethyl) -phenyl) -1-ethenyl) -benzamide 2 (E-2) (4 (Piperidin-1-ylmethyl) phenyl) -1-ethenyl) -N (3 (S) -1-methanesulfonamido-heptan-2-on-3-yl) -benzamide 2 (E-2 (4 ((4 Methylpiperazin-1-yl) methyl) phenyl) -1-ethenyl) -N (3 (S) -l-methanesulfonamido-heptan-2-on-3-yl) -benzamide 2 (E-2 (4 (N, N-Benzyl-methylaminomethyl) phenyl) -1-ethenyl) -N (3 (S) -l-methanesulfonamido-heptan-2-on-3-yl) -benzamide 2 (E-2 (4 (4-ethylpiperazine-1 -ylmethyl) phenyl) -1-ethenyl) - (3 (S) -1-methanesulfonamido-heptan-2-on-3-yl) -benzamide 2 (E-2 (4- (4-Benzylpiperazin-1-ylmethyl) phenyl) ) -1-ethenyl) -1-N (3 (S) -l-methanesulfonamido-heptan-2-on-3-yl) -benzamide N (3 (S) -4-Phenyl-l-methanesulfonamido-butan-2 -on-3-yl) -2 (E-2-phenyl-1-ethane il) -benzamide 2 (E-2 (3, 4-dimethoxyphenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-methanesulfonamido-butan-2-on-3-yl) -benzamide 2 (E-2 (2-Naphthyl) -l-ethenyl) -N (3 (S) -4-phenyl-1-methanesulfonamido-butan-2-on-3-yl) -benzamide 2 (E-2 (4 ( N, N-Dimethylaminomethyl) phenyl) phenyl-1-ethenyl) - (3 (S) -4-phenyl-1-methanesulfonamido-butan-2-on-3-yl) -benzamide 2 (E-2 (4 (N, N-Diethylaminomethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-methanesulfonamido-butan-2-on-3-yl) -benzamide N (3 (S) -4-Phenyl-l-methanesulfonamido-butan-2-on-3-yl) -2 (E-2- (4- (pyrrolidin-1-ylmethyl) -phenyl) -1-ethenyl) -benzamide 2 ( E-2 (4 (Piperidin-1-ylmethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-methanesulfonamido-butan-2-on-3-yl) -benzamide 2 (E -2 (4 ((4-Methylpiperazin-1-yl) methyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-methanesulfon-amido-butan-2-on-3-yl ) -benzamide 2 (E-2 (4 (N, N-Benzyl-methylaminomethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-l-methanesulfon-amido-butan-2-on- 3-yl) -benzamide 2 (E-2 (4- (4-Ethylpiperazin-1-ylmethyl) phenyl) -1-ethenyl) -N (3 (S) -4-phenyl-1-methanesulfon-amido-butan-2 -on-3-yl) -benzamide 2 (E-2 (4- (4-Benzylpiperazin-1-ylmethyl) phenyl) -1-ethenyl) - (3 (S) -4-phenyl-1-methanesulfon-amido-butan -2-on-3-il) -benzamide N (3 (S) -4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl) -2 (E-2- (4-pyridyl) -1-ethenyl) -benzamide N (3 (S) - l-Phenylsulfonamido-heptan-2-on-3-yl) -2 (E-2 (4-pyridyl) -1-ethenyl) -benzamide N (3 (S) -l-Methanesulfonamido-heptan-2-on-3 -yl) -2 (E-2 (4-pyridyl) -1-ethenyl) -benzamide N (3 (S) -Benzamido-heptan-2-on-3-yl) -2 (E-2 (4-pyridyl ) -1-ethenyl) -benzamide N (3 (S) -acetamido-heptan-2-on-3-yl) -2 (E-2 (4-pyridyl) -1-ethenyl) -benzamide N (3 (S) -l-Methanesulfonamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4-pyridyl) -1-ethenyl) -benzamide N (3 (S) - l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4-pyridyl) 1-ethenyl) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4-pipdil ) -1-ethenyl) -benzamide N (3 (S) -l-Methanesulfonamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (2-pyridyl) -1-ethene ) -benzamide N (3 (S) -4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl) -2 (E-2 (2-pyridyl) -1-ethene) -1-benzamide N ( 3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (2-pyridyl) -1-ethenyl) -benzamide N (3 (S) -l- Benzamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (2-pyridyl) -1-etheyl) -benzamide N (3 (S) -l-Phenylsulfonamido-heptan-2 -on-3-yl) -2 (E-2 (2-pyridyl) -1-ethenyl) -benzamide N (3 (S) -l-Methansulfonam? do-heptan-2-on-3-yl) -2 (E-2 (2-pyridyl) -1-ethenyl) -benzamide N (3 (S) -l-Benzamido-heptan-2-on-3-yl) -2 (E-2 (2-pyridyl) -1 -etenyl-benzamide N (3 (S) -l-Acetamido-heptan-2-on-3-? l) -2 (E-2 (2-pyridyl) -1-ethenyl-benzamide N (l-Benzamido-heptan -2-on-3-yl) -2 (E-2-phenyl-l-ethenyl) -benzamide N (l-Benzamido-heptan-2-on-3? L) -2 (E-2 (3, 4-dimethoxy? Phenyl) -1- ethenyl) -benzamide N (l-Benzamido-heptan-2-on-3-yl) -2 (E-2 (2-naphthyl) -1-ethenyl) -benzamide N (l-Benzamido-heptan-2-on- 3-yl) -2 (E-2 (4 (N, N-dimethylaminomethyl) -phenyl) -1-ethene) -1-benzamide N (l-Benzamido-heptan-2-on-3-? L) -2 (E-2 (4 (N, N-diethylamino ethyl) -phenyl) -1-ethenyl) -benzamide N (l-Benzamido-heptan-2-on-3-yl) -2 (E-2 (4 (pyrrolidin -1-ylmethyl) -phenyl) -1-ethenyl) -benzamide N (l-Benzamido-heptan-2-on-3-yl) -2 (E-2 (4 (p? Peridm-1-ylmethyl) -phenyl) ) -1-ethenyl) -benzamide N (l-Benzam? Do-heptan-2-on-3-yl) -2 (E-2 (4 ((-methylpiperazin-1-yl) -ethyl) phenyl) -1 -etenyl) -benzamide N (l-Benzamido-heptan-2-on-3-yl) -2 (E-2 (4 (N, N-benzyl-methylaminomethyl) phenyl) -1-ethenyl) -benzamide (l- Benzamido-heptan-2-on-3-yl) -2 (E-2- (4- (4-ethylpiperazin-1-methylmethyl) phenyl) -1-ethenyl) -benzamide (l-Benzamido-heptan-2-on-3 -yl) - (E-2 (4 (4-bncylpiperazin-1-ylmethyl) phenyl) -1-ethenyl) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -2 (E-2 phenyl-l-ethenyl) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -2 (E-2 (3, 4-dimethoxy? Phenyl) -1-ethenyl) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -2 (E-2 (2-naphthyl) -1-ethenyl) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -2 (E-2 (4 (N, N-dimethylaminomethyl) -phenyl) -1-ethenyl) -benzamide N (l-Acetamido-heptan-2) -on-3-yl) -2 (E-2 (4 (N, N-diethylaminomethyl) phenyl) -1-ethenyl) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -2 ( E-2 (4 (pyrrolidin-1-ylmethyl) -phenyl) -1-ethenyl) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -2 (E-2 (4 (piperidin-1) -ylmethyl) -phenyl) -1-ethenyl) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -2 (E-2 (4 ((4-methylpiperazin-1-yl) -methyl) phenyl) -1-ethenyl) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -2 (E-2 (4 (N, N-benzyl-methylaminomethyl) phenyl) -1-ethenyl) - Benzamide N (l-Acetamido-heptan-2-on-3-? l) -2 (E-2 ((4-ethylpiperazin-l-ylmethyl) phenyl) -1-etheno) -benzamide N (l-Acetamido) -heptan-2-on-3-yl) -2 (E-2- (4- (4-benzylpiperazin-1-ylmethyl) phenyl) -1-ethenyl) -benzamide N (l-Benzamido-hexan-2-on-3 -yl) -2 (E-2-phenyl-1-ethenyl) -benzamide N (l-Benzamido-hexan-2-on-3-yl) -2 (E-2 (3,4-dimethoxyphenyl) -1- ethenyl) -benzamide N (l-Benzamido-hexan-2-on-3-yl) -2 (E-2 (2-naphthyl) -1-et enyl) -benzamide N (l-Benzamido-hexan-2-on-3-yl) -2 (E-2 (4 (N, N-dimethylaminomethyl) -phenyl) -1-ethenyl) -benzamide N (l-Benzamido) -hexan-2-on-3-? l) -2 (E-2 (4 (N, N- diethylaminomethyl) -phenyl) -1-ethenyl) -benzamide N (l-Benzamido-hexan-2-on-3-yl) -2 (E-2 (4 (pyrrolidin-1-ylmethyl) -phenyl) -1-ethenyl ) -benzamide N (l-Benzamido-hexan-2-on-3-yl) -2 (E-2 (4 (piperidin-1-ylmethyl) -phenyl) -1-ethenyl) -benzamide N (l-Benzamido- hexan-2-on-3-yl) -2 (E-2 (4 ((4-methyl-piperazin-1-yl) -methyl) -phenyl) -1-ethenyl) -benzamide N (1-Benzamido-hexan-2) on-3-yl) -2 (E-2 (4 (N, N-benzyl-methylaminomethyl) phenyl) -1-ethene) -1-benzamide N (l-Benzamido-hexan-2-on-3-yl) -2 (E-2 (4- (4-ethylpipeazin-1-ylmethyl) phenyl) -1-ethenyl) -benzamide N (l-Benzamido-hexan-2-on-3-yl) -2 (E-2 (4 (4-benzylpiperazin-1-ethyl) phenyl) -1-ethenyl) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (2-phenyl-1-ethenyl) -benzamide N (3 (S) -l-Acetamido-heptan-2-on-3-yl) -2 (E-2 (3,4-dimethoxyphenyl) -1-ethenyl) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-? l) -2- (E-2 (2-naphthyl) -1-ethenyl) -benzamide N (( 3S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4 (N, N-di-methylaminomethyl) phenyl) -1-e tenyl) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4 (N, Nd? -ethylamino ethyl) phenyl) -1 -etenyl) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2- (4-pyrrolidin-1-ylmethyl) -phenyl) -1-ethenyl ) -benzamide (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4 (piperidin-1-ylmethyl) phenyl) -1-ethenyl) -benzamide N ( 3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4 ((4-methylpiperazin-1-yl) methyl) phenyl) -1-ethenyl) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4 (N, N-benzyl-methylaminomethyl) phenyl) -1-ethenyl ) -benzamide (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4- (4-ethylpiperazin-1-ylmethyl) phenyl) -1-ethenyl ) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4 (4-benzylpiperazin-1-ylmethyl) phenyl) -1- etenil) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 (E-2-phenyl-l-ethenyl) -benzamide N (3 (S) -l-Benzamido -heptan-2-on-3-yl) -2 (E2- (3,4-dimethoxyphenyl) -1-ethenyl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on -3-yl) -2 (E-2 (2-naphthyl) -1-ethenyl) -benzamide N ((3S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 ( E-2 (4N, N-Di-ethylaminomethyl) phenyl) -1-ethenyl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 (E -2 (4 (N, N-di-ethylaminomethyl) phenyl) -1-ethenyl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 ( E-2 (4 (pyrrolidin-1-ylmethyl) -phenyl) -1-ethenyl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 ( E-2 (4 (piperidin-1-ylmethyl) phenyl) -1-ethenyl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 (E -2 (4 ((4- methyl-piperazin-1-yl) methyl) -phenyl) -1-ethenyl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-? L) -2 (E-2 (4 (N, N-benzyl-methylaminomethyl) -phenyl) -1-ethenyl ) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4 (4-et? lpiperazin-1-ylmethyl) phenyl) - 1-ethenyl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2 (E-2 (4 (4-benzylpiperazin-1-ylmethyl) -fen ) -1-ethenyl) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylmethoxy) -benzamide N (l-Acetamido-heptan-2-on-3- il) -4 (naft-2-ylmethoxy?) -benzamide N (3 (S) -l-Methanesulfonylamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylmethoxy) -benzamide N (1-methansulfonylamido-heptan-2-on-3 il) -4 (naft-2-ylmethoxy?) -benzamide 4 (Naphth-2-ylmethoxy) -N (3 (S) -l-phenylsulonylamido-4-phenyl-butan-2-on-3-yl) -benzamide 4 (Naft-2-ylmethoxy) - (1-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl ) -4 (naphth-2-ylmethoxy) -benzamide N (l-Benzamido-heptan-2-on-3-yl) -4 (naphth-2-ylmethoxy) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylmethylmercapto) -benzamide N (l-Acetamido-heptan-2-on-3- il) -4 (naft-2-ylmethylmercapto) -benzamide N (3 (S) -l-Methanesulfonylamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylmethylmercapto) -benzamide (l-methanesulfonylamido-heptan-2-on-3-yl) ) -4 (naphth-2-ylmethylmercapto) -benzamide 4 (Naphth-2-ylmethylmercapto) -N (3 (S) -l-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide. (Naft-2-ylmethylmercapto) - (l-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylmethylmercapto) -benzamide N (l-Benzamido-heptan-2-on-3-yl) -4 (naphth-2-ylmethylmercapto) -benzamide N (3 (S) -l-Acetamido-4 -phenyl-butan-2-on-3-yl) -2-phenoxy-benzamide N (l-Acetamido-heptan-2-on-3-yl) -2-phenoxy-benzamide N (3 (s) -l- Methansulfonylamido-4-phenyl-butan-2-on-3-yl) -2-phenoxy-benzamide N (1-methanesulfonylamido-heptan-2-on-3-yl) -2-phenoxy-benzamide 2-Phenoxy- (3 (S) -l-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide 2-Phenoxy-N (l-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2-phenoxy-benzamide N (l-Benzamido-heptan-2-on-3-yl) -2- phenoxy-benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -4 (naft-2- ilamido) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -4 (naphth-2-ylamido) -benzamide N (3 (S) -l-Methanesulfonylamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylamido) -benzamide N (l-methanesulfonylamido-heptan-2-on-3- il) -4 (naphth-2-ylamido) -benzamide 4 (Naphth-2-ylamido) -N (3 (S) -l-phenylsulfon-lido-4-phenyl-butan-2-on-3-? l) -benzamide 4 (Naphth-2-ylamido) - (l-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3 -yl) -4 (naphth-2-ylamido) -benzamide N (l-Benzamido-heptan-2-on-3-yl) -4 (naphth-2-ylamido) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylsulfonamido) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -4 (naphth-2-l-sulfonamido) -benzamide N (3 (S) -l-Methanesulfonylamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylsulfonamido) -benzamide N ( l-Methansulfonylamido-heptan-2-on-3-yl) -4 (naphth-2-ylsulfonamido) -benzamide 4 (Naphth-2-ylsulfonamido) -N (3 (S) -l-phenylsulfonylamido-4-phen ? l-butan-2-on-3-yl) -benzamide 4 (Naft-2-ylsulfonamido) -N (l-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -4 (naphth-2-ylsulfonamido) -benzamide N (l-Benzamido-heptan-2-on-3- il) -4 (naphth-2-ylsulfonamido) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -3- (naphth-2-ylsulfonamido) -benzamide N (l-Acetamido-heptan-2-on-3-yl) -3 (naphth-2-ylsulfonamido) -benzamide N (l-Methanesulfonyl-ammon-2-yn-3-yl) -3- (naphth-2) -sulfonsulfone gone) -benzamide 3 (Naphth-2-ylsulfonamido) -N (l-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (l-Benzamido-heptan-2-on-3-yl) - 3 (naphth-2-ylsulphonamido) -benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -3-phenylsulfonamido-benzamide (l-Acetamido-heptan- 2-on-3-yl) -3-phenylsulfonamido-benzamide N (3 (S) -l-Methanesulfon-lam? Do-4-phenyl-butan-2-on-3-yl) -4-phenylsulfonamido-benzamide N (l-Methanesulfonylamido-heptan-2-on-3-yl) ) -3-phenylsulfonamido-benzamide 3-Phenylsulfonamido-N (3 (S) -l-phenylsulfonamido-4-phenyl-butan-2-on-3-? L) -benzamide 3-Phenylsulfonamido-N (l-phenylsulfonylamido-heptan -2-on-3-il) -benzamide N (3 (S) -l-Benzam? Do-4-phenyl-butan-2-on-3-yl) -3-phenylsulfone-ido-benzamide N (l-Benzamido-heptan-2-on-3-yl) -3-phenylsulfonamido-benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2-phenyl-benzamide N (l-Acetamido-heptan-2-on-3-yl) -2- phenyl-benzamide N (3 (S) -l-Methanesulfonylamido-4-phenol-butan-2-on-3-yl) -2-phenyl-benzamide N (l-Methanesulfonylamido-heptan-2-on-3- il) -2-phenyl-benzamide 2-Phenyl-N (3 (S) -l-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide 2-Phenyl-N (l-phenylsulfonylamido) -heptan-2-3-il) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -2-phen-1-benza ida N (l-Benzamido-heptan-2-on-3-yl) -2-phenyl-benzamide 2- (4 (N, N-Dimethylaminomethyl) -phenyl) -N (3 (S) -l-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide 2- (4 (N, N-Diethylaminomethyl) -phenyl) -N (3 (S) -1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide N (3 (S) -l -Fenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -2- (4-pyrrolidin-1-ylmethyl) -phenyl) -benzamide N (3 (S) -l-Acetamido-4-phenyl -butan-2-on-3-yl) -3-qumolin-8-ylsulfonamido) -benzamide N (l-Acetamid-O-heptan-2-on-3-yl) -3 (quinolin-8-ylsulfonamido) -benzamide á-S y¿Ís ^^ 3 (quinolm-8-ylsulfonamido) - (3 (S) -l-methanesulfonylamido-4-phenol-butan-2-on-3-yl) -benzamide 3 (quinolin-8-ylsulfonamido) - (1) -metanesulfonylamido-heptan-2-on-3-yl) -benzamide 3 (quinolin-8-illsulfonamido) -N (3 (S) -1-phenylsulfonylamido-phen-1-butan-2-on-3-yl) - benzamide 3 (quinolin-8-ylsulfonamido) -N (l-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Benzamido-4-phen-1-butan-2-on -3-yl) -3 (quinolin-8-ylsulfonamido) -benzamide (l-Benzamido-heptan-2-on-3-yl) -3-phenylsulfonamido-benzamide 2- (4- (N, N-D? Methylaminomethyl) phenoxy-N (3 (S) -1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide 2- (4- (N, N-Dimethylaminomethyl) phenoxy-N (1-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide 2- (4- (N, N-Diethylaminomethyl) phenoxy-N (3 (S) -1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide 2- (4- (N, N-Diethylaminomethyl) phenoxy- (1-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Phenylsulfonylamido-4-phenyl-butan-2- on-3-yl) -2 (4-pyrrolidin-1-ylmethyl) phenoxy-benzamide (1-phenylsulfomlamide-do-heptan-2-on-3-yl) -2- (4-p? rroidin-1-yl) ) -phenoxy-benzamide N (4-Cyclohex? II-phenylsulfonamido-butan-2-on-3-yl) -2 (E-2 (4 (N, Nd? methylaminomethyl) -phenyl) -1-ethenyl) -benzamide (4-Cyclohexyl-1-phenylsulfonamido-butan-2-on-3-yl) -2 (E ((N, N-diethylaminomethyl) -phenyl) -1-ethene) -1-benzamide N (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -2 (E-naphtho-2-yl-1-ethenyl) -benzamide N (l-Acetamido-heptan- 2-on-3-yl) -2 (E-naphtho-2-yl-l-ethenyl) -benzamide N (3 (S) -l-methanesulfonylamido-4-phenyl-butan-2-on-3- il) -2 (E-naphtho-2-yl-l-ethenyl) -benzamide N (l-Methanesulfonylamido-heptan-2-on-3-yl) -2 (E-naphtho-2-yl-l-ethenyl) -benzamide 2 (E-Naphtho-2-yl-l-ethenyl) -N (3 (S) -l-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide 2 (E-Naphtho- 2-yl-l-ethenyl) -N (l-phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on- 3-yl) -2 (E-naphtho-2-yl-1-ethene) -1-benzamide N (l-Benzamido-heptan-2-on-3-yl) -2 (E-naphtho-2-yl- 1-ethenyl) -benzamide 2 (E-2-Benzoyl-1-ethenyl) -N (3 (S) -l-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl) -benzamide N (3 ( S) -l-Acetamido-4-phenol-butan-2-on-3-yl) -6-methyl-4 (naphth-2-ylamido) -benzamide (l-Acetamido-heptan-2-on-3 -yl) -6-methyl-4 (naphth-2-ylamido) -benzamide N (3 (S) -l-methanesulfonylamido-4-phenyl-butan-2-on-3-yl) -6- methyl-4 (naphth-2-ylamido) -bertisamide N (l-Methanesulfonylamido-heptan-2-on-3-yl) -6-methyl-4 (naphth-2-ylamido) -benzamide 6-Methyl-4 (naphth-2-ylamido) -N (3 (S) -l-phenylsulfonylamido-4-5-phenyl-butan-2-on-3-yl) -benzamide 6-Methyl-4 (naphth-2-ylamido) -N (l-Phenylsulfonylamido-heptan-2-on-3-yl) -benzamide N (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -6-met-l-4 (naphth-2-ylamido) -benzamide 10 N (l-Benzamido-heptan-2-on-3-yl) -6-methyl-4 (naphth-2-ylamido) -benzamide 3 (N (3 (S) - 4-Phenyl-l-phenylsulfonamido-butan-2-on-3-yl) -4-carbamoyl-phenyl) -naphtho [c] pyrimidione 3 (N- (3 (S) -l-Benzam? Do-4-phenyl) -butan-2-on-3-yl) -4- 15 carbamoylphenyl) -naphtho [c] pyrimidione 3 (N- (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl ) -4- carbamoylphenyl) -naphtho [c] pyrimidione 3 (N (3 (S) -l-Methanesulfonamido-4-phenyl-butan-2-on-3-yl) -4-carbamoylphenyl) -naphtho [c] pyrimidione 20 3 (N (l-Phenylsulfonamido-heptan-2-on-3-yl (-4-carbamoylphenyl) -naphtho [c] pyrimidione 3 (N- (l-Benzamido-heptan-2-on-3-yl) - 4-carbamoylphenyl) - Naphtho [Cypyrimidione 3 (N- (l-Acetamido-4-phenyl-heptan-2-on-3-yl) -4- 25 carbamoylphenyl) -naphtho [c] pyrimidione , * ». • 3 (N (l-Methanesulfonamido-heptan-2-on-3-yl) -4-carbapentelphenyl) naphtho [c] pyrimidione 2 (N (3 (S) -4-Phenyl-1-phenylsulfonam? Do- butan-2-on-3-? l) -4- carbamoylphenyl) -benzo [c] phthalimide 2 (N- (3 (S) -l-Benzamido-4-phenyl-butan-2-on-3-yl) -4- carbamoylphenyl) -benzo [c] phthalimide 2 (N- (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -4- carbamoylphenyl) -benzo [c] phthalimide 2 (N (3 (S) -l-Methanesulfonamido-4-phenyl-butan-2-on-3-? L) -4-carbamoylphenyl) -benzo [c] phthalimide 2 (N (l-Phenylsulfonamide) -heptan-2-on-3-yl) -4-carbamoylphenyl) -benzo [c] phthalimide 2 (N- (l-Benzamido-heptan-2-on-3-yl) -4-carbamoylphenyl) -benzo [c ] phthalimide 2 (N- (l-Acetamido-4-phenyl-heptan-2-on-3-yl) -4- carbamoylphenyl) -benzo [c] phthalimide 2 (N (l-Methanesulfonamido-heptan-2-on- 3-yl) -4-carbamo? Lfen? L) - benzo [c] phthalimide 2 (N (3 (S) -4-Phenyl-l-phenylsulfonamido-butan-2-on-3-yl) -3-carbamoyl -6-methyl-phenyl) -benzo [c] phthalimide 2 (N- (3 (S) -l-Benzamido-4-phenol-butan-2-on-3-yl) -3-carbamoyl- 6-methyl-phenyl) -benzo [c] phta li 2 (N- (3 (S) -l-Acetamido-4-phenyl-butan-2-on-3-yl) -3-carbamoyl-6-methyl-phenyl) -benzo [c] phthalimide 2 (N (3 (S) -l-Methanesulfonamido-4-phenyl-butan-2-on-3-yl) -3- carbamoyl-6-methyl-phenyl) -benzo [c] phthalimide 2 (N (l-Phenylsulfonamido-heptan-2-on-3-yl) -3-carbamoyl-6-methyl-phenyl) -benzo [c] phthalimide 2 (N- (l-Benzamido-heptan-2-on-3-yl) -3-carbamoyl-methyl-phenyl) -benzo [c] phthalimide 2 (N- (l-Acetamido-4-phenyl-heptan-2- on-3-? l) -3-carbamoyl-6-methyl-phenyl) -benzo [c] phthalimide 2 (N- (l-methanesulfonamido-heptan-2-on-3-yl) -3-carbamoyl-6-) methyl-phenyl) -benzo [c] phthalimide

Claims (12)

1. A benzamide of formula I: and its tautomeric forms, the possible enanitomeric and diastereomeric forms, the E and Z forms, and possible physiologically tolerated salts, in which the variables have the following meanings: R C6-C6 alkyl, branched or unbranched, where one of the C atoms in this chain may be substituted by a phenyl ring, cyclohexyl ring, indolyl ring and an SCH3 group, and the phenyl ring in turn is substituted for a maximum of two radicals R, where R is hydrogen, C 1 -C 4 alkyl, branched or unbranched, -O-C 1 -C 4 alkyl, OH, Cl, F, Br, I, CF 3, N 2, NH 2, CN , COON, COO-C1-C4 alkyl, NHCO-C1-C4 alkyl, and R2 can be NR5CO-R6 and NHR5S02-R6, and is chlorine, bromine, fluorine? Ci-Cß alkyl, NHCO-C1-C4 alkyl, NHS02-C1-C4 alkyl, N02, -O-C?-C4 alkyl, CN, COOH, CONH2, COO C1-C4 alkyl, S02-alkyl of C1-C4, S02Ph, S02NH-C1-C4 alkyl, iodine, S02NH2 and NH2, and it can be aromatic rings and heteroaromatic rings such as naphthyl, quinolmyl, quinoxalyl, benzimidazolyl, benzothienyl, quinazolyl, phenyl, thienyl, imidazolyl, pyridyl, pyrimidyl and pyridazyl, it being possible also that the rings be substituted by R and up to two radicals R, and B is a bond, - (CH2) n-, - < CH2) m-0- (CH2) or-, - < CH2) 0-S- (CH2) m-, - (CB2) or-S0- < CrI2) m-, - (CH2) or-S02- (CH2) ", -, -CH-CH-, -CC-, -CO-CH = CH-, - (CH2) or -CO- (CH2), , -, -lCa2) m-tHHC0- (CH2) o-, - (CH2) m-CONH- (CH2) o-, - (CH2) m-NHS02- (CH2) 0-, -NH-CO-CH = CH-, - (CH2) m-S02) MH- (CH2) 0-, AB together also: is hydrogen and C1-C4 alkyl, and is hydrogen, phenyl, naphthyl, C 1 -C 6 alkyl, linear or branched, it being possible for a C atom in the chain to be substituted by a phenyl ring which may also be substituted by one or two radicals R, and it can be hydrogen, branched or unbranched C1-C4 alkyl, -O-C1-C4 alkyl, OH, Cl, F, Br, I, CF3, N02, NH2, CN, COOH, COO-C1-C4 alkyl , NHCO-C1-C4 alkyl, phenyl, NHCO-femlo, -NHS02-C1-C4 alkyl, -NHS02-phenol, -S02-C1-C4 alkyl, pyridine [sic] and S02-phenyl . is hydrogen, -CHR - (CH2) p-R where R is pyrrolidine [sic], morpholine [sic], pipe idina [sic], hexahydroazepine [sic], homopiperazine [sic] and R [lacuna] Ci-Cß alkyl, branched or unbranched, and which may also bear a phenyl ring which in turn is substituted by a maximum of two R radicals, where R is hydrogen, C1-C4 alkyl, branched or unbranched, -O-C1-C4 alkyl, OH, Cl, F, Br, I, CF3, N02, NH2, CN, COOH, COO-C1-C4 alkyl, NHCO-C1-C4 alkyl, -NHS02-CJ.-C4 alkyl and -? 02- C1-C4 alkyl; Y R is hydrogen and Ci-Cß alkyl, branched or unbranched, and n, p is, independent of each other, a number 0, 1 or 2, and m, or is, independent of each other, a number 0, 1, 2, 3 or 4.

2. The benzamide of formula I as claimed in claim 1, wherein: i-B ^ a.4; «! - '« iíaBg¿ is phenyl and naphthyl, each of which may be substituted by R, and is -S02NH-, -CH = CH-, a bond and -C = C- and ethyl, propyl, butyl and benzyl, R2 is NH-S02-R6 and NH-CO-R6 and R is hydrogen and COOH, and R is C 1 -C 4 alkyl, branched or unbranched, [sic] and phenyl, and R9 is hydrogen, -CHR14-R12, where R12 is pyrrolidine, morfolma, pipepdma -NR10R13 and > CH ^ -2 N N- IO and C-Cβ alkyl, branched or unbranched, and R can is C 1 -C 4 alkyl, branched or unbranched. 14 R can be hydrogen, methyl, ethyl.

3. The benzamide of formula I as claimed in claim 1, wherein: A is phenyl and naphthyl, each of which may be substituted by R, and B is -S02NH-, -CH = CH-, a bond and -C = C- and ethyl, propyl, butyl and benzyl, is NH-S02-R6 and NH-CO-R6 and is hydrogen and COOH, and R is C 1 -C 4 alkyl, branched or unbranched, [sic] and phenyl, and is hydrogen, -CHR -R, where R is pyrrolidine, morpholine, piperidine -NR10R13 and ¿CH ^ h-2 N N Rio and R C -C alkyl, branched or unbranched, and R is C 1 -C 4 alkyl, branched or unbranched. 14 R can be hydrogen, methyl, ethyl.

4. A benzamide of formula I as claimed in claim 1, wherein g A is phenyl which may also be substituted by R, and B is -CH = CH-, and radical B is in the ortho position the benzamide of general formula I, and R is butyl and benzyl, R2 is NH-S02-R6, and it's hydrogen, and R is C 1 -C 4 alkyl, branched and unbranched, [sic] and phenyl, and R is hydrogen, -CH2-RX, where R is pyrrolidine, morpholma, pipepdma, -R10R13 and W1-2 -N N-RIO and C-Cβ alkyl, branched or unbranched, and aafe- .. R can be C1-C4 alkyl, branched or unbranched.

5. The use of benzamides of the formula I as mentioned in claims 1-4 to treat diseases.

6. The use of benzamides of the formula I as mentioned in claims 1-4 as inhibitors of cysteine proteases.

7. The use of benzamides of the formula I as claimed in claim 7 [sic] as inhibitors of cysteine proteases such as calpains and cathepsins, in particular calpains I and II and cathepsins B and L.

8. The use of benzamides of the Formula I as claimed in claims 1-4 for production as [sic] drugs to treat diseases in which calpain activities increase.

9. The use of benzamides of formula I as claimed in claims 1-4 to produce drugs to treat neurodegenerative diseases and neuronal damage.

10. The use as claimed in claim 9, to treat neurodegenerative diseases and neuronal damage caused by trauma ischemia or massive hemorrhage.

11. The use as claimed in claim 9, for treating cerebrovascular accident and cerebral skull trauma.

12. Use as claimed in claim 9, for treat Alzheimer's disease and Huntington's disease. The use as claimed in claim 9, for treating epilepsies. The use of the compounds of formula I as claimed in claims 1-4 to produce drugs to treat damage to the heart after cardiac ischemia and damage due to reperfusion after vascular occlusions. The use of the compounds of the formula I as claimed in claims 1-4 to produce drugs to treat damage to the kidneys after renal ischemia. The use of the compounds of formula I as claimed in claims 1-4 to produce drugs to treat damage arising from the proliferation of smooth muscle cells and to treat restenosis of blood vessels after angioplasty. The use of the compounds of formula I as claimed in claims 1-4 to produce medicaments for treating cerebral spasms and coronary vasospasms. The use of benzamides of the formula I as claimed in claims 1-4 to produce medicaments for treating tumors and metastases thereof. The use of benzamides of formula I as claimed in Á-fc, claims 1-4 to produce medicaments for treating diseases in which the concentrations of methylleukin-1 are elevated. The use of benzamides of the formula I as claimed in claims 1-4 to treat immunological abnormalities such as inflammation and rheumatic disorders. A preparation of medicament for oral, parenteral or mtraperitoneal use, containing, per unit dose, in addition to the traditional auxiliary pharmaceutical substances, at least one benzamide I as claimed in claims 1-3. SUMMARY OF THE INVENTION A benzamide of formula I: and its tautomeric forms, the possible enanitomeric and diastereophatic forms, the E and Z forms, and possible physiologically tolerated salts, in which the variables have the following meanings: R Cj-Cß alkyl, branched or unbranched, where one of the C atoms in this chain may be substituted by a phenyl ring, cyclohexyl ring, indolyl ring and an SCH3 group, and the phenyl ring in turn is 4 4 substituted for a maximum of two radicals R, where R is hydrogen, C 1 -C 4 alkyl, branched or unbranched, -O-C 1 -C 4 alkyl, OH, Cl, F, Br, I, CF 3, N 2, NH 2, CN , COON, COO-C1-C4 alkyl, NHCO-alkyl C1-C4, and R2 can be NR5CO-R6 and NHR5S02-R6, and R is chlorine, bromine, fluorine, C?-C6 alkyl, NHCO-C1-C4 alkyl, NHS02-C1-C4 alkyl, N02, -O-C?-C4 alkyl, CN, COOH, CONH2, COO C1-C4 alkyl, S02-C1-C4 alkyl, S02Ph, S02NH-C1-C4 alkyl, iodine, S02NH2 and NH2, and it may be aromatic rings and heteroaromatic rings such as naphthyl, quinolinyl, quinoxalyl, benzimidazolyl, benzothienyl, quinazolyl, phenyl, thienyl, imidazolyl, pyridyl, pyrimidyl and pyridazyl, it also being possible for the rings to be substituted by R and up to two radicals R, and is a bond, - (CH2) "-, - (CH2)" - 0- (CH2) o-, - < CH2) o-S- (CH2) n-, - (CH2) o-S0- (CH2) -, - < CH2) o-S02- (CH2) m-, -CH-CH-, -CC-, -CO-CH = CH-, - (CH2) 0-CO- (CH2) m- (- < CH2) m -NHC0- (CH2) o-, - (CH2) m-C0NH- (CH2) o-, - (CH2) n-NHS02- < CH2) o-f -NH-CO-CH-CH-, - (CH2) m-S02NH- (CH2) o-, A-B together as well: is hydrogen and C1-C4 alkyl, and is hydrogen, phenyl, naphthyl, C?-C6 alkyl, linear or branched, it being possible for a C atom in the chain to be substituted by a phenyl ring which may also be substituted by one or two radicals R, and it can be hydrogen, branched or unbranched C1-C4 alkyl, -O-C1-C4 alkyl, OH, Cl, F, Br, I, CF3, N02, NH2, CN, COOH, COO-C1-C4 alkyl , NHCO-C1.-C4 alkyl, phenyl, NHCO-phenyl, -NHS02-C1-C4 alkyl, -NHS02-phenyl, -S02-C1-C4 alkyl, pyridine [sic] and S02-phenyl. is hydrogen, -CHR14- (CH2) P-R12 where R12 is pyrrolidine [sic], morpholine [sic], piperidine [sic], hexahydroazepma [sic], homopiperazine [sic]) l-2-NR10R13 and > CH -N - io and R [lacuna] C6-C6 alkyl, branched or unbranched, and which can also bear a phenyl ring which in turn is substituted by a maximum of two radicals R1, where R is hydrogen, C1-6alkyl C4, branched or unbranched, -O-C1-C4 alkyl, OH, Cl, F, Br, I, CF3, N02, NH2, CN, COOH, COO-C1-C4 alkyl, NHCO-C1- alkyl C4, -NHS02-C1-C4 alkyl and -S02- C1-C4 alkyl; Y R is hydrogen and C1-C6 alkyl, branched or unbranched, and n, p is, independent of each other, a number 0, 1 or 2, and m, or is, independent of each other, a number 0, 1, 2, 3 or 4.