SK15062000A3 - Novel heterocyclically substituted amides with cysteine protease-inhibiting effect - Google Patents

Abstract

The invention relates to amides of the general formula (I), which are inhibitors of enzymes, especially cysteine proteases.

Description

Technical field

The present invention relates to novel amides which are enzyme inhibitors, in particular cysteine proteases such as calpain (= calcium dependent cysteine protease) and its isoenzymes and cathepsins, for example B and L.

BACKGROUND OF THE INVENTION

Calpains are intracellular proteolytic enzymes of the cysteine protease family and are found in many cells. Calpains are activated by increasing calcium concentration, distinguishing calpain I or μ-calpain, which is activated by micromolar concentrations of calcium ions, and calpain II or m-calpain, which is activated by millimolar concentrations of calcium ions (P. Johnson, Int. J. Biochem) 1990, 22 (8), 811-22). Other calpain isoenzymes have also been 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 cleavage of regulatory proteins such as protein kinase C, cytoskeletal proteins such as MAP 2 and spectra, muscle proteins, protein degradation in rheumatoid arthritis, platelet activation proteins, neuropeptide metabolism, proteins in mitosis, and others reported in MJ Barrett et al., Life Sci. 1991, 48, 1659-69 and K. K. Wang et al., Trends in Pharmacol. Sci., 1994, 15, 412-9.

Elevated calpain levels have been measured in various pathophysiological processes, for example: ischemia of the heart (e.g. myocardial infarction), kidney or central nervous system (e.g. stroke), inflammation, muscular dystrophy, cataracts of the eyes, central nervous system injury (e.g. trauma), Alzheimer's disease, etc. (see above reference to K.K. Wang). There is a suspicion that there is a link between these disorders and elevated and persistent intracellular calcium levels. This results in an over-activation of calcium-dependent processes which are no longer subject to physiological control. Accordingly, excess activation of calpains can also induce pathophysiological processes.

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It has therefore been postulated that inhibitors of calpain enzymes may be useful in the treatment of these disorders. Various studies have confirmed this. For example, Seung-Chyul Hong et al., Stroke 1994, 25 (3), 663-9 and R. T. Bartus et al., Neurological Res. 1995, 17, 249-58 have shown the neuroprotective effect of calpain inhibitors in acute neurodegenerative disorders or ischemia that occur, for example, after stroke. Similarly, calpain inhibitors improved recovery from memory impairment and neuromotor disorders that occurred following experimental brain trauma (K. E. Saatman et al. Proc. Natl. Acad. Sci. USA, 1996, 93-3433). Edelstein, C. L., et al., Proc. Natl. Acad. Sci. USA, 1995, 92, 7662-6 found a protective effect of calpain inhibitors on kidneys damaged by hypoxia. Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59 (1), 40-8, have shown that calpain inhibitors exhibit beneficial effects following cardiac damage caused by ischemia or reperfusion. Since calpain inhibitors inhibit the release of the βAP4 protein, it has been suggested for potential use as therapeutic agents in Alzheimer's disease (J. Higaki et al., Neuron, 1995, 14, 651-59). Similarly, calpain inhibitors inhibit the release of interleukin-1a (N. Watanabe et al., Cytokine 1994, 6 (6), 597-601). In addition, calpain inhibitors have been found to have cytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int. Breast Cancer Res., Sendai Jp, 1994, 25-28 September, Int. J. Oncol., 5 (Suppl.), 1994, 381).

Other possible uses for calpain inhibitors are given in K.

K. Wang, Trends in Pharmacol. Sci., 1994, 15, 412-8.

Calpain inhibitors have already been described in the literature. However, they are predominantly irreversible or peptide inhibitors. Irreversible inhibitors are generally alkylating agents and have the disadvantage that they act nonselectively or are unstable in the body. Thus, these inhibitors often have undesirable side effects, such as toxicity, and are therefore of limited use or unusable. Irreversible inhibitors include, for example, E 64 epoxides (EB McGowan et al., Biochem. Biophys. Res. Commun. 1989, 158, 432-5), α-haloketones (H. Angliker et al., J. Med. Chem. 1992, 35, 216-20) or disulfides (R. Matsueda et al., Chem. Lett. 1990, 191-194).

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Many known reversible inhibitors of cysteine proteases, such as calpain, are peptide aldehydes, especially dipeptide or tripeptide aldehydes, for example ZVal-Phe-H (MDL 28170) (S. Mehdi, Trends in Biol. Sci. 1991, 16, 150-3). ). Under physiological conditions, peptide aldehydes have the disadvantage that, due to their high reactivity, they are often unstable, can be rapidly metabolized and are susceptible to non-specific reactions that can cause toxic effects (J.A. Fehrentz and B. Castro, Synthesis 1983, 676-78).

JP 08183771 (CA 1996, 605307) and EP 520336 disclose aldehydes that are derived from 4-piperidinecarboxamides and 1-carbonyl-4-piperidinecarboxamides as calpain inhibitors. The aldehydes described in the present invention, which are derived from amides of general structure I with heteroaromatic substituents, have not yet been described.

Peptide ketone derivatives are also inhibitors of cysteine proteases, particularly calpaines. Thus, for example, it is known that ketone derivatives where the ketone group is activated by an electron acceptor group such as CF3 are serine protease inhibitors. In the case of cysteine proteases, derivatives with ketones activated by CF ₃ or similar groups have little or no activity (MR Angelastro et al., J. Med. Chem. 1990, 33, 11-13). To date, it has been found that only ketone derivatives in which, on the one hand, leaving groups in position cause irreversible inhibition and, on the other hand, the ketone group is activated by a carboxylic acid derivative are effective calpain inhibitors (see MR Angelastro et al., Supra; (11850; WO 92/12140; WO 94/00095 and WO 95/00535). However, only peptide derivatives of these ketoamides and ketoesters have been reported to be effective (Zhaozhao Li et al., J. Med. Chem. 1993, 36, 3472-80; S. L Harbenson et al., J. Med. Chem. 1994, 37). , 2918-29 and see above, MR Angelastro et al.).

Ketobenzamides have already been described in the literature. For example, the ketoester PhCO-AbuCOOCH ₂ CH ₃ has been described in WO 91/09801, WO 94/00095 and WO 92/11850. The analogous phenyl derivative Ph-CONH-CH (CH ₂ Ph) -CO-COCOOCH ₃ is according to MR Angelastro et al., J. Med. Chem. 1990, 33, 11-13, only a weak calpain inhibitor. This derivative is also described in JP Burkhardt, Tetrahedron Leti, 1988, 3433-36. However, the importance of substituted benzamides has never been studied.

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In several therapies, for example stroke therapy, the active ingredients are administered intravenously, for example, as an infusion solution. In order to do this, it is necessary to have substituents, in this case calpain inhibitors, which have adequate water solubility in order to prepare an infusion solution. However, many of the disclosed calpain inhibitors have the disadvantage that they have little or no solubility in water and are therefore unsuitable for intravenous administration. Active ingredients of this type can only be administered with water solubility adjuvants (R.T. Bartus et al. J. Cereb. Blood FlowMetab. 1994, 14, 537544). However, these excipients, such as polyethylene glycol, often have side effects or are even incompatible. A non-peptide calpain inhibitor that is water-soluble without excipients would therefore be a great advantage. Such an inhibitor has not been described so far and would therefore be new.

In the present invention, substituted non-peptide aldehydes, ketocarboxylic esters and keto amide derivatives are described. These compounds are novel and surprisingly show the possibility of obtaining potent non-peptide inhibitors of cysteine proteases such as calpain by incorporating rigid structural fragments. Moreover, all of the compounds of formula I have at least one aliphatic amine radical and are thus capable of forming acid salts. A large number of these substances are soluble in water in a 0.5% solution at pH 0.4-5 and thus exhibit the desired profile for intravenous administration, which is required, for example, in stroke therapy. SUMMARY OF THE INVENTION

The present invention relates to amides of formula I

and their tautomeric and isomeric forms, possible enantiomeric and diastereomeric forms, as well as possible physiologically tolerated salts, wherein the variables have the following meanings:

G ·······································

R ¹ can be hydrogen, C 1 -C ₆ -alkyl, branched and unbranched, phenyl, naphthyl, quinolyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinazolyl, quinoxalyl, thienyl, benzothienyl, benzofuranyl, furanyl and indolyl, which rings may also be substituted with up to three R ⁶ radicals, and

R ² is hydrogen, C, -C6-alkyl, branched or unbranched, O-Ci-C6-alkyl, branched or unbranched, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C ^ Ce-alkyl phenyl, C2-C6-alkenyl-phenyl , C 2 -C 6 -alkynylphenyl, OH, Cl, F, Br, I, CF 3, NO 2, NH 2, CN, COOH, COO-C 1 -C 4 -alkyl, NHCO-C 1 -C 4 -alkyl, NHCO-phenyl, CONHR ⁹ , NHSO 2 Cl -C ₄ -alkyl, NHSO ₂ -phenyl, SO ₂ -C 1 -C ₄ -alkyl and SO ₂ -phenyl and

R ³ can be NR ⁷ R ⁸ or a ring as

R -θ. _{; ;}

ΊΜ (R ®) n

(R ⁶ ) n —N

(R ⁶ ) n

N (R ⁶ ) n

R ⁴ is -C 1 -C 6 -alkyl, branched or unbranched, which may also carry phenyl, pyridyl or naphthyl, which in turn is substituted by a maximum of two R ⁶ radicals, and

R ⁵ is hydrogen, COOR ¹¹ and CO-Z, wherein Z is NR ¹² R ¹³ and N, -NN-R ⁷

W

-N

R7

R ⁶ is hydrogen, C 1 -C ₄ -alkyl, branched or unbranched, -O-C 1 -C ₄ -alkyl, OH, Cl, F, Br, I, CF ₃ , NO _2, NH ₂ CN, COOH, COO-C 1 -C ₄ -alkyl, -NHCO-C 1 -C ₄ -alkyl, -NHCO-phenyl, -NHSO ₂ -C ₁ -C ₄ -alkyl, -NHSO ₂ -phenyl, -SO ₂ -C ₁ -C ₄ -alkyl and -SO ₂ phenyl and

R ⁷ is hydrogen, C 1 -C ₆ -alkyl, which is linear or branched, and which may be substituted by phenyl, which may itself be substituted by one or two R ¹⁰ radicals, and ··

R ⁸ is hydrogen, C 1 -C ₆ -alkyl, which is linear or branched, and which may be substituted with phenyl, which may itself be substituted with one or two R ¹⁰ radicals, and

R ⁹ is hydrogen, C 1 -C ₆ -alkyl, branched or unbranched, which may also carry R ¹⁶ , or phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, naphthyl, quinolyl, imidazolyl, which may also carry one or two R ¹⁴ , a

R ¹⁰ can be hydrogen, C 1 -C 4 -alkyl, branched or unbranched, -O-C 1 -C 4 -alkyl, OH, Cl, F, Br, I, CF ₃ , NO ₂ , NH ₂ , CN, COOH, COO-C , -C ₄ -alkyl, -NHCO-C 1 -C 4 alkyl, -NHCO-phenyl, -NHSO ₂ -C 1 -C 4 -alkyl, -NHSO ₂ -phenyl, -SO ₂ -C 1 -C ₄ -alkyl and -SO _2- phenyl

R ¹¹ is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may be substituted with phenyl, which may itself be substituted with one or two R ¹⁰ radicals, and

R ¹² is hydrogen, C 1 -C ₆ -alkyl, branched and unbranched, and

R ¹³ is hydrogen, C 1 -C ₆ -alkyl, which is branched or unbranched, which in addition may be substituted by a phenyl ring, which may additionally carry a radical R ¹⁰ and

R ¹⁴ is hydrogen, C 1 -C 6 -alkyl, branched or unbranched, -O-C 1 -C 6 -alkyl, branched or unbranched, OH, Cl, F, Br, I, CF 3, NO 2, NH 2, CN, COOH, COO- C 1 -C 4 -alkyl, or two R ¹⁴ radicals may be an OC (R ¹⁵ ) 2 O bridge, and

R ¹⁵ is hydrogen, C ₁ -C ₆ -alkyl, branched and unbranched, and

R ¹⁶ may be phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, pyrrolyl, naphthyl, quinolyl, imidazolyl, which may also carry one or two substituents R ⁶ , and

A is - (CH _{2) m} -, - (CH _{2) m} -O- (CH _{2) o} -, - (CH _{2) 0} -S- _{(CH2) m} -, - (CH _{2) a} -SO - (CH ₂ ) _m -, - (CH ₂ ) _O SO ₂ - (CH ₂ ) _m -, -CH = CH-, -C§C-, -CO-CH = CH- _I - (CH ₂ ) _o -CO- (CH _{2) m} -, - (CH _{2) m} NHCO (CH _{2) o} -, - (CH _{2) m} -CONH- (CH _{2) o} -, - (CH _{2) m} -NHSO ₂ - _(CH2) -, -NH-COCH = CH-, - (CH _{2) m} -SO ₂ -NH- (CH _{2) o} -, -CH = CH-CONH- and

R ¹ -A together are also a

B is phenyl, pyridine, pyrimidine, pyrazine, imidazole and thiazole and x is 1, 2 or 3 and n is 0, 1 or 2, and m, o are independently 0, 2, 3 or 4.

The compounds of formula I may be used as racemates, as enantiomerically pure compounds, or as diastereomers. If enantiomerically pure compounds are needed, they can be obtained, for example, by carrying out a conventional resolution of the racemates with the compounds of formula I or intermediates thereof using a suitable optically active base or acid. On the other hand, enantiomeric compounds can also be prepared using commercially available compounds, for example optically active amino acids, for example phenylalanine, tryptophan and tyrosine.

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9

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9

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9

999 99 ·

The invention also relates to compounds which are mesomers or tautomers of compounds of formula I, for example compounds wherein the aldehyde or keto group in formula I is in the form of an enol tautomer.

The invention further relates to physiologically tolerated salts of the compounds I, which can be obtained by reacting the compounds I with a suitable acid or base. Suitable acids and bases are disclosed, for example, in Fortschritte der Arzneimittelforschung, 1966, Birkhäuser Verlag, Vol. 10, p. 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, and the like. and sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.

The amides I of the invention can be prepared by various methods outlined in the synthesis scheme.

Synthesis scheme

The heterocyclic carboxylic acids II are combined with the appropriate amino alcohols III to give the corresponding amides IV. For this, conventional peptide coupling methods are described in detail either in RC Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972 et seq., Or in HoubenWeyl, Methoden der organischen Chemie, 4th edition, E5, Chapter V. It is preferred to use "activated" acid derivatives II where the COOH acid group is converted to a COL group. L represents a leaving group such as Cl, imidazole and N-hydroxybenzotriazole. This activated acid is then reacted with samines to give amides IV. The reaction is carried out in anhydrous inert solvents such as dichloromethane, tetrahydrofuran and dimethylformamide at temperatures from -20 to +25 ° C.

These alcohol derivatives IV can be oxidized to the aldehyde derivatives i according to the invention. Various conventional oxidation reactions (see RC Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 et seq.) Can be used for this, such as Swern oxidation and oxidation analogous to Swern oxidation (TT Tidwelt, Synthesis, 1990, 857-70). sodium hypochlorite / TEMPO (SL Harbenson et al., supra) or Dess-Martin (J. Org. Chem. 1983, 48, 4155). The reaction is preferably carried out here. in inert aprotic solvents such as dimethylformamide, tetrahydrofuran or dichloromethane with oxidizing agents such as DMSO / pyridine x SO ₃ or DMSO / oxalyl chloride at temperatures from -50 to +25 ° C depending on the method (see references above).

Alternatively, the carboxylic acid II can be reacted with aminohydroxamic acid derivatives VI to form benzamides VII. In this case, the reaction is carried out as in Preparation IV. Hydroxamic derivatives VI can be obtained from protected amino acids by reaction with hydroxylamine. Also in this case, the process described above for the preparation of amides is used. Removal of the protecting group X, for example Boe, is carried out in the usual manner, for example with trifluoroacetic acid. The amide hydroxamic acids VII obtained in this way can be converted by reduction to the aldehydes I according to the invention. For this purpose, for example, lithium aluminum hydride is used as a reducing agent at -60 to 0 ° C in inert solvents such as tetrahydrofuran or ether.

Analogously to the last process, carboxylic acids or acid derivatives can also be prepared, for example esters IX (P = COOR ', COSR'), which can also be converted to the aldehydes I according to the invention by reduction. These procedures are described in R.

C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, pages 619-26.

The amides I of the invention having heterocyclic substituents and having a ketoamide or ketoester group can be prepared by a variety of methods as outlined in Synthesis Schemes 2 and 3.

If desired, carboxylic acid esters lia are converted to acids II with acids or bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an aqueous medium or in mixtures consisting of water and organic solvents such as alcohols or tetrahydrofuran at a temperature of room temperature or at elevated temperature, e.g. 25-100 ° C.

These acids II are coupled to the α-amino acid derivative using conventional conditions as described, for example, in Houben-Weyl, Methoden der organischen.

Chemie, 4th Ed., E5, Chapter V and R.C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, Chap. 9th

For example, carboxylic acids II are converted to "activated" acid derivatives IIb = Y-COL, where L is a leaving group such as Cl, imidazole and N-hydroxybenzotriazole, and then converted to derivative XI by reaction with the amino acid derivative H ₂ N-CH ( R ³ ) -COOR. This reaction is carried out in anhydrous inert solvents such as dichloromethane, tetrahydrofuran and dimethylformamide at temperatures from -20 to +25 ° C.

Scheme 1

R ¹ —A OR '(R ² ) _n —B — Z

Í O

R ¹ OH N (R 2) n - B-Z

Oh (Ha)

R ¹ —A

R4 (R2) _{n -} B - CONH - - - COOR C (XI)

R 4 (R 2) n -B-CONH 2

R ¹ —A (H)

COOR

R ¹ —A

R4 (R2) n-B-CONH-COOH C

C = R ³ - (CH ₂ ) _X Derivatives XI, which are usually esters, can be converted to ketocarboxylic acids XII analogously to the above-described hydrolysis. Ketoesters 1 'are prepared by a reaction analogous to the Dakin-West reaction according to the method of ZhaoZhao Li et al., J. Med. Chem., 1993, 36, 3472-80. In this process, carboxylic acids such as XII are reacted with oxalic acid monoester chloride at elevated temperature (50-100 ° C) in solvents such as tetrahydrofuran, and the products so obtained are then reacted with bases such as sodium ethoxide in ethanol at 25- 80 ° C to give the ketoesters 1 'of the invention. Ketoesters l

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can be hydrolyzed as described above, for example, to the ketocarboxylic acids of the invention.

The reaction to give the ketobenzamides I 'is carried out analogously to the method of ZhaoZhao Li et al. (see above). The keto group in I 'is protected by the addition of 1,2-ethanedithiol using Lewis acid catalysis, for example with boron trifluoride etherate, in internal solvents such as dichloromethane at room temperature to give the dithiane. These derivatives react with amines R ³ -H in polar solvents such as alcohols at temperatures of 0 to 80 ° C to give ketoamides I (R ⁴ = NR ⁷ R ⁸ ).

Scheme 2

C = R ³ - (CH ₂ ) _x An alternative method is shown in Scheme 2. Ketocarboxylic acids II are reacted with aminohydroxycarboxylic acid derivatives XIII (for preparation XIII see SL Harbenson et al., J. Med. Chem. 1994, 37, 2918-29 or JP Burkhardt et al Tetrahedron Lett. 1988, 29, 3433-3436) using conventional peptide synthesis methods (see above, Houben-Weyl) to yield amides

• · · • ···· • • · · • · • · • · · • · · • · • · • · · • • · • é • • · • ·· · • · · · · · · · · · ·

XIV. These alcohol derivatives XIV can be oxidized to the ketocarboxylic acid derivatives I according to the invention. Various conventional oxidation reactions (see RC Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 et seq.) Can be utilized here, for example Swern oxidation and analogous oxidations, preferably dimethylsulfoxide / pyridine sulfur trioxide complex in solvents such as dichloromethane or tetrahydrofuran, if necessary with the addition of dimethylsulfoxide, at room temperature or at -50 to 25 ° C (TT Tidwell, Synthesis 1990, 857-70) or sodium hypochlorite / TEMPO (SL Harbenson et al., supra).

In the case of α-hydroxy esters XIV (X = O-alkyl), these can be hydrolyzed to carboxylic acids XV by similar methods, but preferably with lithium hydroxide in mixtures of water and tetrahydrofuran at room temperature. Other esters or amides XVI are prepared by reaction with alcohols or amines under the above synthetic conditions. The alcohol derivative XVI can be oxidized to the ketocarboxylic acid derivatives I according to the invention.

The preparation of carboxylic esters II has already been described in some cases, otherwise it can be carried out by conventional chemical methods.

Compounds in which X is a bond are prepared by conventional aromatic coupling, for example by Suzuki synthesis with boric acid derivatives and halides with palladium catalysis, or by copper catalyzed synthesis of aromatic halides. The alkyl-bridged radicals (X = - (CH _{2) m} -) can be prepared by reducing the analogous ketones or by alkylating the organolithium, e.g. orphiphenyloxazolidines or other organometallic compounds (IM Dordor et al., J. Chem. Soc. Perkin Trans. I, 1984, 1247-52).

Ether-bridged derivatives are prepared by alkylation of the corresponding alcohols or phenols with halides.

Sulfoxides and sulfones can be obtained by oxidation of the corresponding thioethers.

Alkene and alkyne bridged compounds are prepared, for example, by the Hep reaction of aromatic halides and the corresponding alkenes and alkynes (I. Sakamoto et al., Chem. Pharm. Bull., 1986, 34, 2754-59).

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Chalkones are prepared by condensation of acetophenones with aldehydes and can be converted, if desired, to analogous alkyl derivatives by hydrogenation.

Amides and sulfonamides are prepared from amine and acid derivatives analogously to the methods described above.

Dialkylaminoalkyl substituents are obtained by reductive amination of aldehyde derivatives with suitable amines in the presence of borohydrides, for example BHs / pyridine complex or NaBH ₃ CN (AF Abdel-Magid, CA Maryanoff, KG Carson, Tetrahedron Lett. 1990, 31, 5595; AE Moormann, Synth. Commun., 1993, 23, 789).

The heterocyclic-substituted amides I according to the invention are inhibitors of cysteine proteases, in particular cysteine proteases, for example calpaines I and II and cathepsins B and L.

The inhibitory effect of amides I with heterocyclic substituents was determined by enzyme assays known in the literature, which determine as the criterion of effect the concentration of inhibitor which inhibits 50% of the enzyme activity (= IC 50). Amides I were measured in this way for calpain I inhibitory effect, calpain II and cathepsin B.

Cathepsin B test

Inhibition of cathepsin B was determined by a method analogous to S. Hasnain et al., J. Biol. Chem., 1993, 268,235-40.

μΙ of inhibitor solution prepared from inhibitor and DMSO (final concentrations: 100 μΜ to 0,01 μΜ) are added to 88 μΙ of cathepsin B (human liver cathepsin (Calbiochem) diluted to 5 units in 500 μΜ buffer). This mixture is preincubated at room temperature (25 ° C) for 60 minutes and then the reaction is started by adding 10 μΙ of 10 mM Z-Arg-Arg-pNA (in buffer containing 10% DMSO). The reaction is monitored in a microplate reader at 405 nm for 30 minutes. IC ₅₀ values of calpain I and II are then determined from the maximum gradients

The inhibitory properties of the calpain inhibitors were tested in a buffer containing 50 mM Tris-HCl, pH 7.5; 0.1 M NaCl; 1 mM dithiothreitol;

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0.11 mM CaCl ₂ , using Suc-Leu-Tyr-AMC fluorogenic calpain substrate (25 mM dissolved in DMSO, Bachem, Switzerland). Human μ-calpain is isolated from erythrocytes and the enzyme with a purity of> 95%, evaluated by SDS-PAGE, Western blot analysis and N-terminal sequencing, is obtained after several chromatographic steps (DEAE-Sepharose, phenyl-Sepharose, Superdex 200 and blue). Sepharose). The fluorescence of the cleavage product - 7-amino-4-methylcoumarin (AMC) is followed Spex Fluorolog fluorimeter at _λβ Χ = 380 nm and = 460 nm. The cleavage of the substrate is linear over a measurement interval of 60 minutes and the autocatalytic activity of calpain is low when the tests are performed at 12 ° C. Inhibitors and calpain substrate are added to the assay mixture as solutions in DMSO, with a final DMSO concentration not exceeding 2%.

To the test mixture, add 10 μΙ of substrate (total 250 μΜ) and then 10 μΙ μ-calpain (total 2 ng / ml, i. E.

nM). The calpain-mediated cleavage of the substrate is measured for 15-20 min.

Then, 10 μ (inhibitor (50 -100 μ v solution in DMSO) is added and the inhibition of cleavage is measured for a further 40 min.

The K i values are determined using the classical reversible inhibition equation:

K = 1 (v / v) -1; where I = inhibitor concentration, v ₀ = initial rate prior to inhibitor addition; Vj = reaction rate at equilibrium.

The rate is calculated from v = AMC release / time, i. height / time.

Calpain is an intracellular cysteine protease. Calpain inhibitors must cross the cell wall to prevent calpain from degrading intracellular proteins. Some known calpain inhibitors, such as E 64 and leupeptin, only pass poorly through the cell walls and accordingly show little effect on cells, although they are good calpain inhibitors. The goal is to find compounds that have a better ability to cross membranes. Human platelets are used to demonstrate the ability of membrane inhibitors to cross membranes.

Calpain-mediated degradation of pp60src tyrosine kinase in platelets

After platelet activation, pp60src tyrosine kinase is cleaved by calpain. This has been studied in detail by Oda et al. in J. Biol. Chem., 1993, Vol. 268, 12603-12608. This study showed that pp60src cleavage can be prevent calpeptin, which is an inhibitor of calpain. The cellular activity of the novel substances was tested according to this publication. Fresh human blood with the addition of citrate was centrifuged at 200 g for 15 min. Platelet-rich plasma was collected and diluted 1: 1 with platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KCl, 0.5 mM MgCl ₂ x ₆ H ₂ O, 0.24 mM NaH ₂ PO ₄ xH ₂ O, 12 mM _NaHCO3, 5.6 mM glucose, 1 mM EDTA, pH 7.4). After centrifugation and washing with platelet buffer, platelets were adjusted to a concentration of 10 ⁷ cells / ml. Human platelets were isolated at room temperature.

In the assay mixture, isolated platelets (2x10 ⁶ ) were preincubated at 37 ° C for 5 min with different concentrations of inhibitors (dissolved in DMSO). Platelets were then activated with 1 μΜ of A23187 ionophore and 5 mM CaCl ₂ . After 5 minutes of incubation, the platelets were centrifuged briefly at 13,000 rpm. and blended 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% glycerol and 1% SDS). Proteins were fractionated in a 12% gel and pp60src and its 52 kDa and 47 kDa cleavage products were identified by Western Blotting. The polyclonal rabbit anti-Cys-src antibody used (pp60 ^c ' ^src ) was obtained from Biomol Feinchemikalien (Hamburg). This primary antibody was detected with a second goat antibody coupled to HRP (Boehringer Mannheim, FRG). Western blotting was performed according to known methods.

The cleavage of pp60src was quantified by densitometry using controls inactivated (Control 1: no cleavage) and ionophore and calcium-treated platelets (Control 2: corresponds to 100% cleavage). ED »corresponds to the concentration of inhibitor at which the color reaction intensity is reduced by 50%.

Glutamate-induced cell death in cortical neurons

The assay was performed as described in Choi D. W., Maulucci-Gedde M. A. and Kriegstein A. R., "Glutamate neurotoxicity in cortical cell culture". J. Neurosci.

1989, 7, 357-368.

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Half of the cortex was excised from 15 day old mouse embryos and individual cells were obtained enzymatically (trypsin). These cells (glia and cortical neurons) were seeded in 24-well plates. After three days (laminin-coated platelets) or seven days (ornithine-coated platelets), mitosis is performed by FDU (5-fluoro-2-deoxyuridine). 15 days after cell preparation, cell death is induced by the addition of glutamate (15 min). After glutamate is removed, calpain inhibitors are added. After 24 hours, cell damage was assessed by determining lactate dehydrogenase (LDH) in the cell culture supernatant.

It has been postulated that calpain is also involved in apoptoic 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). For this reason, cell death was induced in another model, the human cell line, by calcium in the presence of a calcium ionophore. Calpain inhibitors must reach the inside of the cell and inhibit calpain there to prevent induced cell death.

Calcium-mediated cell death in NT2 cells

In NT2 human cells, calcium death in the presence of ionophore A 23187 can be initiated. 20 hours before the experiment, 10 ⁵ cells per well are plated in microtiter plates. After this time, the cells were incubated with different inhibitor concentrations in the presence of 2.5 μΜ ionophore and 5 mM calcium. After 5 hours, 0.05 mL of XTT (Cell Proliferation Kit II, Boehringer Mannheim) was added to the reaction mixture. The optical density was determined approximately 17 hours later according to the manufacturer's instructions on the SLT Easy Reader EAR 400. The optical density at which half of the cells died was calculated from two non-inhibitor cell controls after incubation in the absence and presence of ionophore.

Increased glutamate activity, which leads to states of excessive arousal or central nervous system (CNS) toxic effects, occurs in several neurological diseases or mental disorders. The effects of glutamate are mediated by various receptors. Two of these receptors are classified by specific agonists as NMDA receptor and AMPA receptor. Agonists of these glutamate-mediated effects can thus be used for the treatment of these disorders, in particular for therapeutic use in neurodegenerative disorders. · · · · · · · · · · · · · · · · · · · · · · · · ··· · · · ··· ···

..............

such as Huntington's disease and Parkinson's disease, neurotoxic disorders following hypoxia, anoxia, ischemia and lesions such as stroke and trauma lesions, or as anti-epileptics (Arzneim. Forschung 1990, 40, 511-514; TIPS, 1990, 11, 334-). 338;

Drugs of the Future 1989, 14, 1059-1071).

Protection against excessive cerebral excitation by excitatory amino acids (NMDA and AMPA antagonism in mice)

Intracerebral administration of excitatory amino acids (EAA) induces such drastic excessive excitation that leads to convulsions and death of animals (mice) within a short time. These symptoms can be inhibited by systemic, e.g. by intraperitoneal administration of centrally acting agents (EAA antagonists). Since excessive activation of EAA receptors in the central nervous system plays an important role in the pathogenesis of various neurological disorders, it can be concluded, based on the established EAA antagonism in vivo, that these agents may have therapeutic utility in such CNS disorders. The ED ₅₀ was determined as a measure of efficacy of these substances, in which 50% of the animals did not experience symptoms following a previous ip administration of a measured substance with a fixed dose of NMDA or AMPA.

Heterocyclic-substituted amides I are inhibitors of cysteine proteases such as calpain I and II and cathepsin B and L and can therefore be used to control diseases associated with increased activity of calpain enzymes or cathepsin enzymes. Thus, the present amides I can be used to treat neurodegenerative diseases occurring after ischemia, trauma, subarachnoid haemorrhage and stroke, and neurodegenerative disorders such as multi-infarct dementia, Alzheimer's disease, Huntington's disease and epilepsy, and, in addition, to treat cardiac damage after cardiac damage, skeletal muscle damage, muscular dystrophy, damage due to proliferation of smooth muscle cells, coronary vasospasms, cerebral vasospasms, eye cataracts and vascular restenosis after angioplasty. In addition, amides I may be useful in the chemotherapy of tumors and their metastases and in the treatment of disorders in which elevated levels of interleukin-1 occur, such as inflammation and rheumatic disorders.

The pharmaceutical compositions of the invention consist of a therapeutically effective amount of compounds I and conventional pharmaceutical excipients.

• Β ·· Β

For topical topical use, for example in powders, ointments or sprays, the active compounds may be present in the usual concentrations. The active ingredients are generally present in an amount of from 0.001 to 1% by weight, preferably from 0.001 to 0.1% by weight.

For internal use, the preparations are administered in single doses. From 0.1 to 100 mg per kg of body weight is administered in a single dose. The formulations may be administered daily in one or more doses depending on the nature and severity of the disease.

In addition to the active ingredient, the pharmaceutical compositions of the invention contain conventional vehicles and diluents suitable for the desired mode of administration. For topical external use, pharmaceutical excipients such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycostearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum and lanolin can be used. Suitable examples for internal use are lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.

Antioxidants such as tocopherol and butylated hydroxyanisole as well as butylated hydroxytoluene, flavoring agents, stabilizers, emulsifiers and lubricants may also be present.

The substances contained in the preparation in addition to the active compound, as well as the substances used in the manufacture of pharmaceutical preparations, are toxicologically harmless and compatible with the active ingredient concerned. The pharmaceutical preparations are prepared in a customary manner, for example by mixing the active ingredient with other conventional carriers and diluents.

The pharmaceutical preparations can be administered in various ways, for example orally, parenterally, for example by intravenous infusion, subcutaneously, intraperitoneally and topically. Thus, possible dosage forms include tablets, emulsions, infusion solutions, injectable solutions, pastes, ointments, gels, creams, solutions, powders and sprays.

• 9 9 9 • • • • • • • • • • 9 9 9 9

9 9 9 9 9

9 9 · · 9 9 9

999 9,999,999,999

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2 - ((4-phenylpiperazin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide

a) Methyl 2- (4-phenyl-1-piperazinylmethyl) benzoate

10.0 g of methyl 2-chloromethylbenzoate, 15 g of potassium carbonate, 8.8 g of N-phenylpiperazine and a spatula tip of 18-crown-6 in 200 ml of DMF were heated at 100 ° C for 5 hours and then stirred at room temperature for 60 hours. Excess potassium carbonate was filtered off, the filtrate was concentrated and the residue was partitioned between water and ethyl acetate. Drying of the organic phase over magnesium sulfate and removal of the solvent gave 16.8 g (100%) of the product.

b) 2- (4-Phenyl-1-piperazinylmethyl) benzoic acid

16.8 g of intermediate 1a were added to 150 ml of THF and 1.7 g of LiOH in 150 ml of water was added at room temperature. The cloudy solution was clarified by the addition of 10 mL of MeOH. The reaction mixture was stirred at room temperature for 12 hours and hydrolyzed with an equimolar amount of 1 M HCl. The reaction mixture was evaporated to dryness and the residue was dissolved in a mixture of methanol and toluene. Removal of the solvent gave 15.2 g (86%) of the product still containing salt.

c) 2 - ((4-Phenylpiperazin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-ol-2-yl) amide

3.0 g of intermediate 1b and 3 ml of triethylamine were added to 50 ml of DMF. 5 g of sodium sulfate was added and the mixture was stirred for 30 minutes. At 0 ° C, 1.5 g phenylalaninol, 1.4 g HOBT and 2.1 g EDC were added sequentially and the mixture was stirred at room temperature overnight. The reaction mixture was poured into distilled water, basified with NaHCO ₃ , saturated with NaCl, and extracted three times with 100 mL of dichloromethane. The organic phases were washed twice with water and dried over magnesium sulfate. Removal of the solvent gave 2.5 g (59%) of the product.

d) 2 - ((4-Phenylpiperazin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

2.3 g of intermediate 1c was added to 50 ml of DMSO in the presence of 2.4 g of triethylamine and 2.5 g of SO 3 / pyridine complex was added. The mixture was stirred overnight at room temperature. The mixture was poured into 250 ml of distilled water, basified with NaHCO 3, saturated with NaCl, extracted three times with 100 ml of dichloromethane and the organic phase was dried over magnesium sulfate. After removal of the solvent, the residue was dissolved in THF and the hydrochloride was precipitated with HCl in dioxane. The precipitate was filtered off with suction and washed several times with ether to give 1.9 g (71%) of the product.

¹ H-NMR (d ₆ -DMSO): δ = 2.9 (2H), 3.0-3.3 (8H), 4.1-4.5 (2H), 4.7 (1H), 6 , 8-7.7 (14 H),

9.3 (1H), 9.8 (1H) ppm.

Example 2

2 - ((4-Benzylpiperazin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide

a) Methyl 2- (4-benzyl-1-piperazinylmethyl) benzoate

10.0 g of methyl 2-chlorobenzoate and 9.6 g of N-benzylpiperazine were reacted in 200 ml of DMF in the presence of 15 g of potassium carbonate at 100 ° C analogously to Example 1a to obtain 17.6 g (100%). product.

b) 2 - ((4-Benzyl-1-piperazinyl) methyl) benzoic acid

17.5 g of intermediate 2a in 150 ml of THF was hydrolyzed with 1.6 g of LiOH in 150 ml of water analogously to Example 1b to give 9.1 g (54%) of the product.

c) 2 - ((4-Benzylpiperazin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-ol-2-yl) amide

3.0 g of intermediate 2b was reacted in 60 ml of DMF with 3 ml of triethylamine,

1.5 g of phenylalaninol, 1.3 g of HOBT and 2.0 g of EDC were analogous to Example 1c to give 2.0 g (46%) of the product.

d) 2 - ((4-Benzylpiperazin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide

1.5 g of intermediate 2c was oxidized in 40 ml of DMSO with 1.9 g of SO 3 / pyridine complex in 20 ml of DMSO in the presence of 2.3 ml of triethylamine analogously to Example 1 d to give 0.4 g (21%) of the product in DMSO. form of fumarate.

¹ H-NMR (d ₆ -DMSO): d = 2.1-2.3 (8H), 2.9-3.0 (1H), 3.3-3.6 (6H), 4.5 (1H), 6.6 (2H), 7.1-7.7 (14H), 9.7 (1H), 10.3 (1H) ppm.

Example 3

2 - ((4-Benzylpiperazin-1-yl) methyl) benzoic acid N- (1-carbamoyl-1-oxo-3-phenylpropan-2-yl) amide

a) 2 - ((4-Benzylpiperazin-1-yl) methyl) benzoic acid N- (1-carbamoyl-1-ol-3-phenylpropan-2-yl) amide

1.5 g of intermediate 2b was reacted in 40 ml DMF with 0.7 ml triethylamine, 1.0 g 3-amino-2-hydroxy-4-phenylbutyramide hydrochloride, 0.6 g HOBT and 0.9 g EDC analogously to in Example 1c to give 0.8 g (38%) of the product.

b) 2 - ((4-Benzylpiperazin-1-yl) methyl) benzoic acid N- (1-carbamoyl-1-oxo-3-phenylpropan-2-yl) amide

0.7 g of intermediate 3a was oxidized in 20 ml of DMSO with 0.7 g of SO4-pyridine complex in 20 ml of DMSO in the presence of 0.8 g of triethylamine in analogy to Example 1d to give 0.1 g (18%). of the free base product.

¹ H-NMR (d 6 -DMSO): d = 2.3 (4H), 2.8-3.5 (8H), 5.3 (1H), 6.7-7.5 (16H), 7, Δ (1H), 8.1 (1H), 10.3 (1H) ppm.

Example 4

2- (4 - ((3-methylphenyl) piperazin-1-yl) methyl) benzoic acid N- (1-carbamoyl-1-oxo-3-phenylpropan-2-yl) amide

a) Methyl 2- (4 - ((3-methylphenyl) -1-piperazinyl) methyl) benzoate

4.0 g methyl 2-chloromethylbenzoate and 4.4 g 3-methylphenylpiperazine were heated in 200 ml DMF in the presence of 4.5 g potassium carbonate at 140 ° C for 3 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine, dried over magnesium sulfate and concentrated to give 6.5 g (92%) of the product.

(b) 2- (4 - ((3-Methylphenyl) -1-piperazinyl) methyl) benzoic acid · · · t · t · t · t · ···· · · · · · · ··· · ·· ··· ·· ·

5.9 g of intermediate 4a was dissolved in 75 ml of THF and hydrolyzed with 0.9 g of LiOH in 75 ml of water analogously to Example 1b to give 2.9 g (51%) of the product.

c) 2- (4 - ((3-Methylphenyl) piperazin-1-yl) methyl) benzoic acid N- (1-carbamoyl-1-ol-3-phenylpropan-2-yl) amide

1.8 g of intermediate 4b was added to 50 ml of DMF in the presence of 2.7 ml of triethylamine and 0.8 g of HOBT, followed by the sequential addition of 1.3 g of 3-amino-2-hydroxy-4-phenylbutyramide hydrochloride and 1.2 g of EDC analogously as in Example 1c to give 1.4 g (50%) of the product.

d) 2- (4 - ((3-methylphenyl) piperazin-1-yl) methyl) benzoic acid N- (1-carbamoyl-1-oxo-3-phenylpropan-2-yl) amide

1.2 g of intermediate 4c was dissolved in 30 ml of DMSO and oxidized by

1.6 g of SO3 / pyridine complex in the presence of 1.5 ml of triethylamine analogously to Example 1d, yielding 1.0 g (83%) of the product.

MS: m / e = 484 (M < + >)

The syntheses in Examples 5 and 6 were performed analogously to Example 1.

Example 5

3 - ((4-phenylpiperazin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide fumarate ¹ H-NMR (d ₆ -DMSO): d = 2.5 ( 4H), 2.9 (1H), 3.2 (4H), 3.3 (1H), 3.7 (2H), 4.5 (1H), 6.6 (2H), 6.75 (1H) ), 6.9 (2H), 7.2 (2H), 7.2-7.3 (5H), 7.45 (1H), 7.55 (1H), 7.75 (1H), 7, Δ (2H), 8.9 (1H), 9.7 (1H) ppm.

Example 6

3 - ((4- (2-tert-Butyl-4-trifluoromethylpyrimidin-6-yl) homopiperazin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-yl-2-yl) amide

MS: m / e = 568 (M ⁺ +1).

Example 7 Fl-fl Fl-fl 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7

4- (N- (3,4-dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide

(a) 4- (N- (3,4-dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid

11.5 g of N- (3,4-dioxomethylene) benzyl-N-methylamine and 15.5 g of triethylamine were added to [lacuna] and 15.0 g of 4-bromomethylbenzoic acid in 100 ml of THF were added. The reaction mixture was briefly heated to reflux and then stirred at room temperature for 15 hours. After filtration of the salts, the mother liquor was concentrated, the residue was dissolved in ethyl acetate and washed with water. The aqueous phase was basified and extracted several times with ethyl acetate to give 6.6 g (32%) of the product as a white solid.

b) 4- (N- (3,4-dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid N- (3-phenylpropan-1-ol-2-yl) amide

4.4 g of intermediate 5a was added to 50 ml of DMF in the presence of 2.9 g of triethylamine and 1.8 g of HOBT, 2.0 g of phenylalaninol and 2.8 g of EDC were added sequentially, as in Example 1c, yielding 2 g. 3 g (40%) of the product.

c) 4- (N- (3,4-dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide

2.0 g of intermediate 5b was dissolved in 60 ml of DMSO and oxidized with 2.1 g of SO 3 / pyridine complex in the presence of 1.8 ml of triethylamine analogously to Example 1d to give 1.3 g (68%) of the product. .

¹ H-NMR (CF 3 COOD): d = 2.9 (3H), 3.2 (2H), 4.3-4.9 (5H), 6.1 (2H), 6.6 (1H), 6 9 (3H), 7.2-7.4 (5H), 7.8 (2H), 8.25 (2H) ppm.

MS: m / e = 430 (M < + >)

The syntheses in Examples 8 to 28 were performed analogously to Example 7.

Example 8

4- (N-Benzyl-N-methylaminomethyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide ¹ H-NMR (CF 3 COOD): d = 2.9 (3H), 3.2 ( 2H), 4.3-5.0 (5H), 6.7 (1H), 7.25-7.5 (8H), 7.55 (2H), 7.8 (2H), 8.2 (2H) 2H) ppm.

MS: m / e = 386 (M < ^{+ >} ) &^gt; ee " aaeea " aa aee "

Example 9

4- (N- (4-methoxy) benzyl-N-methylaminomethyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) ¹ H-NMR (CF 3 COOD): d = 2.9 (3H) 3.3 (2H), 4.0 (3H), 4.3-4.9 (5H), 6.7 (1H), 7.1-7.4 (7H), 7.5 (2H) 7.8 (2H), 8.2 (2H) ppm.

MS: m / e = 416 (M < ^{+ >} )

Example 10

4- (N-Benzyl-N-methylaminomethyl) benzoic acid N- (3-butan-1-al-2-yl) amide ¹ H-NMR (CF 3 COOD): d = 1.1 (3H), 1.6 ( 2H), 2.0 (2H), 2.9 (3H), 4.3-4.5 (3H), 4.7 (1H), 4.8 (1H), 6.6 (1H), 7.3-7.6 (5H), 7.8 (2H), 8.3 (2H) ppm.

MS: m / e = 338 (M < + >)

Example 11

4- (N- (3,4-dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid N- (3-butan-1-al-2-yl) amide ¹ H-NMR (CF 3 COOD): d = 1.1 ( 3H), 1.6 (2H), 1.9 (2H), 2.9 (3H), 4.25-4.6 (4H), 4.75 (1H), 6.1 (2H), 6 Δ (1H), 6.9 (3H), 7.8 (2H), 8.3 (2H) ppm.

MS: m / e = 382 (M < ^{+ >} )

Example 12

4- (N- (4-methoxy) benzyl-N-methylaminomethyl) benzoic acid N- (3-butan-1-al-2-yl) amide

MS: m / e = 368 (M < ^{+ >} )

Example 13

4- (N- (3,4-dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid N- (3-cyclohexylpropan-1-al-2-yl) amide ¹ H-NMR (CF 3 COOD): d = 1.0-2, O (13H), 2.9 (3H), 4.3-4.9 (4H), 6.1 (2H), 6.6 (1H),

6.9 (3H), 7.8 (2H), 8.3 (2H) ppm.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · ··

MS: m / e = 436 (M < ^{+ >} ) Example 14

4- (N- (4-benzyl-N-methylaminomethyl) benzoic acid N- (3-cyclohexylpropan-1-al-2-yl) amide ¹ H-NMR (d 6 -DMSO): d = 1.0-1, Δ (13H), 2.1 (3H), 3.4 (2H), 3.5 (2H), 4.3 (1H), 7.1-7.4 (5H), 7.5 (2H) 7.8 (2H), 8.8 (1H), 9.5 (1H) ppm.

Example 15

4- (N- (4-methoxy) benzyl-N-methylaminomethyl) benzoic acid N- (3-cyclohexylpropan-1-al-2-yl) amide ¹ H-NMR (CDCl 3): d = 1.0-1, Δ (13H), 2.1 (3H), 3.4 (2H), 3.5 (2H), 3.7 (3H), 4.3 (1H), 6.8 (2H), 7.25 (2H), 7.5 (2H), 7.9 (2H), 8.8 (1H), 9.5 (1H) ppm.

Example 16

4 - ((2-Phenyl-pyrrolid-1-yl) -methyl) -benzoic acid N- (3-cyclohexyl-propan-1-al-2-yl) -amide MS: m / e = 420 (M *)

Example 17

4 - ((2-Phenylpyrrolid-1-yl) methyl) benzoic acid N- (3-butan-1-al-2-yl) amide MS: m / e = 364 (M +)

Example 18

4 - ((2-phenylpyrrolidin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide MS: m / e = 412 (M ⁺ )

Example 19

4 - ((1,2,3,4-Dihydroquinolin-1-yl) methyl) benzoic acid N- (3-cyclohexylpropan-1-al-2-yl) amide ¹ H-NMR (CDCl 3): d = 1, 0-1.9 (13H), 2.0 (2H), 2.8 (2H), 3.3 (2H), 4.5 (2H), 4.8 (1H),

6.4 (1H), 6.5 (2H), 7.0 (2H), 7.4 (2H), 7.8 (2H), 9.7 (1H) ppm.

• ··············································

MS: m / e = 404 (M < ^{+ >} )

Example 20

4 - ((1,2,3,4-Dihydroquinolin-1-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide ¹ H-NMR (d 6 -DMSO): d = 1.9 (2H), 2.75 (2H), 2.9 (1H), 3.3 (1H), 3.4 (2H), 4.4 (1H),

4.5 (2H), 6.3 (2H), 6.8 (2H), 7.1-7.25 (5H), 7.3 (2H), 7.7 (2H), 8.8 (2H) 1H), 9.5 (1H) PPm.

MS: m / e = 398 (M < ^{+ >} )

Example 21

4 - ((1,2,3,4-Dihydroquinolin-1-yl) methyl) benzoic acid N- (3-butan-1-al-2-yl) amide ¹ H-NMR (d 6 -DMSO): d = 0.9 (3H), 1.2-2.0 (6H), 2.7 (2H), 3.3 (2H), 4.2 (1H), 4.5 (2H),

6.4 (2H), 6.8 (2H), 7.3 (2H), 7.8 (2H), 8.8 (1H), 9.5 (1H) ppm.

MS: m / e = 350 (M < ^{+ >} )

Example 22

4 - ((1,2,3,4-Dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-cyclohexylpropan-1-al-2-yl) amide ¹ H-NMR (d 6 -DMSO): d = 0.9-1.8 (13H), 2.7-2.9 (4H), 3.6 (2H), 3.75 (2H), 4.4 (1H), 6.9-7.1 (4H), 7.4 (2H), 7.8 (2H), 8.8 (1H), 9.5 (1H) ppm.

MS: m / e = 404 (M < + >)

Example 23

4 - ((1,2,3,4-Dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide ¹ H-NMR (d 6 -DMSO): d = 2.7 (2H), 2.8 (2H), 2.9 (1H), 3.2 (1H), 3.5 (2H), 3.7 (2H), 4.5 (1H), 6 9-7.1 (4H), 7.2-7.3 (5H), 7.5 (2H), 7.75 (2H), 8.8 (1H), 9.5 (1H) ppm.

MS: m / e = 398 (M < ^{+ >} )

Example 24 · · · 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24

4 - ((1,2,3,4-Dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-butan-1-al-2-yl) amide hydrochloride ¹ H-NMR (d6 -DMSO): d = 0.9 (3H), 1.2-2.0 (4H), 3.0 (1H), 3.3 (2H), 3.6 (1H), 4.1-4.6 (5H) 7.2 (4H), 7.8 (2H), 8.0 (2H), 9.0 (1H), 9.5 (1H), 11.75 (1H) ppm.

Example 25

N- (3-Cyklohexylpropan-1-al-2-yl) -amide 4 - ((6,7-dimethoxy-1,2,3,4-dihydroisoquinoline-2-yl) methyl) benzoic acid ¹ H-NMR (d -DMSO): d = 0.9-1.9 (13H), 2.7 (4H), 3.4 (2H), 3.6 (3H), 3.65 (2H), 3.7 (3H) ), 4.3 (1H), 6.5 (1H), 6.6 (1H), 7.5 (2H), 7.8 (2H), 8.8 (1H), 9.5 (1H) ppm.

MS: m / e = 464 (M < ^{+ >} )

Example 26

4 - ((6,7-Dimethoxy-1,2,3,4-dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-phenylpropan-1-al-2-yl) amide ¹ H-NMR (de) -DMSO): d = 2.7 (4H), 2.9 (1H), 3.25 (1H), 3.6 (6H), 3.7 (2H), 4.5 (1H),

6.6 (1H), 6.7 (1H), 7.2-7.3 (5H), 7.4 (2H), 7.8 (2H), 8.9 (1H), 9.6 (1H) 1H) ppm.

MS: m / e = 458 (M < ^{+ >} )

Example 27

4 - ((6,7-Dimethoxy-1,2,3,4-dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-butan-1-al-2-yl) amide ¹ H-NMR (d) _6- DMSO): d = 0.9 (3H), 1.4 (2H), 1.5-1.8 (2H), 2.7 (4H), 3.4 (2H), 3.7 (2H) 3H), 3.75 (3H), 3.8 (2H), 4.3 (1H), 6.6 (1H), 6.7 (1H), 7.4 (2H), 7.8 (2H) 8.8 (1H), 9.5 (1H) ppm.

MS: m / e = 410 (M < ^{+ >} )

Example 28

2 - ((1,2,3,4-Dihydroquinolin-1-yl) methyl) benzoic acid N- (3-butan-1-al-2-yl) amide MS: m / e = 441 (M ⁺ )

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71 / ISDG-tcoO

Claims (23)

PATENT CLAIMS 1. The amide of formula (I) · · · Am · • Am Am Am Am Am Am Am Am Am Am Am Am Am Am Am Am And its tautomeric and isomeric forms, possible enantiomeric and diastereomeric forms, and possible physiologically tolerated salts, where the variables have the following meanings: R ¹ can be hydrogen, C 1 -C 6 -alkyl, branched and unbranched, phenyl, naphthyl, quinolyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinazolyl, quinoxalyl, thienyl, benzothienyl, benzofuranyl, furanyl and indolyl, these rings may also be substituted up to three R ⁶ radicals, and R ² is hydrogen, C, -C6-alkyl, branched or unbranched, O-Ci-C6-alkyl, branched or unbranched, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C C6alkylfenyl, C2-C6-alkenyl-phenyl, C2 -C6-alkynylphenyl, OH, Cl, F, Br, I, CF3, NO2, NH2, CN, COOH, COO-C1-C4-alkyl, NHCO-C1-C4-alkyl, NHCO-phenyl, CONHR ⁹ , NHSO2 -C 1 -C ₄ -alkyl, NHSO ₂ -phenyl, SO ₂ -C 1 -C ₄ -alkyl and SO ₂ -phenyl and R ³ can be NR ⁷ R ⁸ or a ring as R ⁴ is -C 1 -C 6 -alkyl, branched or unbranched, which may also carry phenyl, pyridyl, thienyl, cyclohexyl, indolyl or naphthyl, which in turn is substituted by a maximum of two R ⁶ radicals, and R ⁵ is hydrogen, COOR ¹¹ and CO-Z, where Z is NR ¹² R ¹³ and R ⁶ is hydrogen, C 1 -C 4 -alkyl, branched or unbranched, -O-C 1 -C ₄ -alkyl, OH, Cl, F, Br, I, CF ₃ , NO _2, NH ₂ CN, COOH, COO-C 1 -C ₄ -alkyl, -NHCO-C 1 -C ₄ -alkyl, -NHCO-phenyl, -NHSO ₂ -C 1 -C ₄ -alkyl, -NHSO ₂ -phenyl, -SO ₂ -C 1 -C ₄ -alkyl and -SO ₂ phenyl; R ⁷ is hydrogen, C 1 -C ₆ -alkyl, which is linear or branched, and which may be substituted with phenyl, which may itself be substituted with one or two R ¹⁰ radicals, and R ⁸ is hydrogen, C 1 -C ₆ -alkyl, which is linear or branched, and which may be substituted with phenyl, which may itself be substituted with one or two R ¹⁰ radicals, and R ⁹ is hydrogen, C 1 -C ₆ -alkyl, branched or unbranched, which may also carry R ¹⁶ , or phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, naphthyl, quinolyl, imidazolyl, which may also carry one or two R ¹⁴ , a R ¹⁰ can be hydrogen, C 1 -C ₄ -alkyl, branched or unbranched, -OC ₁ -C ₄ -alkyl, OH, Cl, F, Br, I, CF ₃ , NO ₂ , NH ₂ , CN, COOH, COO -C 1 -C ₄ -alkyl, -NHCO-C 1 -C ₄ alkyl, -NHCO-phenyl, -NHSO ₂ -C 1 -C ₄ -alkyl, -NHSO ₂ -phenyl, -SO 4 C 1 -C 4 alkyl and SO ₂ -phenyl R ¹¹ is hydrogen, C 1 -C ₆ -alkyl, linear or branched, and which may be substituted with phenyl, which may itself be substituted with one or two R ¹⁰ radicals, and R ¹² is hydrogen, C 1 -C ₆ -alkyl, branched and unbranched, and R7 = N R7 / -O-O N-R7; R 7 - (CH ₂₎ n ' R8 • · R ¹³ is hydrogen, C 1 -C ₆ -alkyl, which is branched or unbranched, which in addition may be substituted by a phenyl ring, which may additionally carry a radical R ¹⁰ and R ¹⁴ is hydrogen, C 1 -C 6 -alkyl, branched or unbranched, -O-C 1 -C 6 -alkyl, branched or unbranched, OH, Cl, F, Br, I, CF 3, NO 2, NH 2, CN, COOH, COO- C 1 -C 4 -alkyl, or two R ¹⁴ radicals may be an OC (R ¹⁵ ) 2 O bridge, and R ¹⁵ is hydrogen, C 1 -C ₆ -alkyl, branched and unbranched, and R ¹⁶ may be phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, pyrrolyl, naphthyl, quinolyl, imidazolyl, which may also carry one or two substituents R ⁶ , and A is - (CH ₂ ) _m -, - (CH ₂ ) _m -O- (CH ₂ ) _o -, - (CH ₂ ) n - (CH ₂ ) _m -, - (CH ₂ ) n - SO - (CH ₂ ) _m -, (CH ₂ ) _o -SO ₂ - (CH ₂ ) _m -, -CH = CH-, -C = C-, -CO-CH = CH -, - (CH ₂ ) _o -CO- (CH _{2) r} '-, (CH _{2) m} -NHCO- _(CH2) -O-, - (CH _{2) m} -CONH- (CH _{2) o} -, - (CH _{2) m} -NHSO ₂ - (CH ₂₎ -, -NH-CO-CH = CH-, - (CH _{2) m} -SO ₂ -NH- (CH _{2) o} -, -CH = CH-CONH- and B is phenyl, pyridine, pyrimidine, pyrazine, imidazole and thiazole, and x is 1, 2 or 3 and n is 0, 1 or 2, and m, o are independently 0, 1, 2, 3 or 4. • ··············· The amide with heterocyclic substituents of formula I according to claim 1, wherein: B is pyridine or phenyl; and R ⁵ is hydrogen and R ⁹ is hydrogen, C 1 -C ₆ -alkyl, branched or unbranched, which may also carry a substituent R ¹⁶ , R ¹⁶ is phenyl, which may also carry one or two substituents R ¹⁴ , and n is 0 and 1 and x is 1. The amide of heterocyclic substituents of formula I according to claim 1, wherein: B is pyridine or phenyl; and R ⁵ is CONR ¹² R ^13a R ⁹ is hydrogen, C 1 -C 6 -alkyl, branched or unbranched, which may also carry a substituent R ¹⁶ , R ¹⁶ is phenyl, which may also carry one or two substituents R ¹⁴ , and n is 0 and 1 and x is 1. A compound of the formula I according to claim 1, wherein: B is pyridine or phenyl; and R ² is hydrogen R ⁵ is hydrogen and R ⁹ is hydrogen, C 1 -C ₆ -alkyl, branched or unbranched, which may also carry a substituent R ¹⁶ , R ¹⁶ is phenyl, which may also carry one or two substituents R ¹⁴ , and n is 0 and 1 and x is 1. • ··· ······························ The amide of the heterocyclic substituents of formula I according to claim 1, wherein: B is pyridine or phenyl; and R ² is hydrogen R ⁵ is CONR ¹² R ^13a R ⁹ is hydrogen, C 1 -C ₆ -alkyl, branched or unbranched, which may also carry a substituent R ¹⁶ , R ¹⁶ is phenyl, which may also carry one or two substituents R ¹⁴ , and n is 0 and 1 and x is 1. A heterocyclic substituent amide of formula I according to claim 1, wherein: A is - (CH _{2) m} -, - (CH _{2) m} -O- (CH _{2) o} -, - (CH _{2) 0} -S- _{(CH2) m} -, - (CH _{2) m} -CONH - _(CH2) -, -CH = CH-, -C≡C-, - (CH _{2) m} -SO ₂ -NH- (CH ₂₎ - and B is pyridine or phenyl and R ² is hydrogen and R ⁵ is hydrogen and R ⁹ is hydrogen, C 1 -C ₆ -alkyl, branched or unbranched, which may also carry a substituent R ¹⁶ , R ¹⁶ is phenyl and m, n, o is 0 and 1 and x is 1. An amide with heterocyclic substituents of formula I according to claim 1, wherein: A is - (CH _{2) m} -, - (CH _{2) m} -O- (CH _{2) o} -, - _(CH2) "- S- (CH _{2) m} -, - (CH _{2) m} -CONH - _(CH2) -, -CH = CH-, -C≡C-, - (CH _{2) m} -SO ₂ -NH- (CH ₂₎ - and B is pyridine or phenyl and R ² is hydrogen R ⁵ is CONR ¹² R ¹³ and e is hydrogen · · · ··· ··· · ·· ··· ·· ··· R ⁹ is hydrogen, C 1 -C ₆ -alkyl, branched or unbranched, which may also carry a substituent R ¹⁶ , R ¹⁶ is phenyl and m, n, o is 0 and 1 and x is 1. An amide with heterocyclic substituents of formula I according to claim 1, wherein: B is pyridine or phenyl; and R ¹ , R ² are hydrogen and R ⁵ is hydrogen and R ⁹ is hydrogen, C 1 -C 8 -alkyl, branched or unbranched, which may also carry a substituent R ¹⁶ , R ¹⁶ is phenyl and n, o is 0 and x is 1. The amide of heterocyclic substituents of formula I according to claim 1, wherein: B is pyridine or phenyl; and R ¹ , R ² are hydrogen R ⁵ is CONR ¹² R ¹³ a R ⁹ is hydrogen, C 1 -C ₆ -alkyl, branched or unbranched, which may also carry a substituent R ¹⁶ , R ¹⁶ is phenyl and n, o is 0 x is 1. Use of amides of formula I according to claims 1 to 5 for the treatment of diseases. Use of amides of the formula I according to claims 1 to 5 as inhibitors of cysteine proteases. ······················································ · ·· ··· ·· ··· 99 Use according to claim 6 as inhibitors of cysteine proteases such as calpains and cathepsins, in particular calpains I and II and cathepsins B and L. Use of amides of formula I according to claims 1 to 5 for the manufacture of pharmaceuticals for the treatment of diseases in which increased calpain activities occur. Use of amides of formula I according to claims 1 to 5 for the manufacture of pharmaceuticals for the treatment of neurodegenerative disorders and neuronal damage. Use according to claim 9 for the treatment of neurodegenerative disorders and neuronal damage induced by ischemia, trauma or massive bleeding. Use according to claim 10 for the treatment of stroke and craniocerebral trauma. Use according to claim 10 for the treatment of Alzheimer's disease and Huntington's disease. Use according to claim 10 for the treatment of epilepsy. Use of the compounds of formula I according to claims 1 to 5 for the manufacture of pharmaceuticals for the treatment of cardiac damage following cardiac ischemia, renal damage following renal ischemia, skeletal muscle damage, muscular dystrophy, damage due to smooth muscle cell proliferation, coronary vasospasm, eye cataracts and restenosis of vessels after angioplasty. Use of amides of formula I according to claims 1 to 5 for the manufacture of pharmaceuticals for the treatment of tumors and their metastases. Use of amides of formula I according to claims 1 to 5 for the manufacture of a medicament for the treatment of disorders in which elevated levels of interleukin-1 occur. Use of amides according to claims 1 to 5 for the treatment of immunological disorders such as inflammation and rheumatic disorders. Medicament preparation for oral, parenteral or intraperitoneal use, characterized in that it contains at least one benzamide I according to claims 1 to 5 in a single dose in addition to conventional pharmaceutical excipients.