WO1999054320A1 - 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

NEW HETEROCYCLICALLY SUBSTITUTED AMIDES WITH CYSTEIN PROTEASE INHIBITING EFFECT

5 Description

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

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

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

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

Therefore, it has been postulated that inhibitors of calpain enzymes can be useful in the treatment of these diseases. Various studies confirm this. So Seung-Chyul Hong et 2 al., Stroke 1994, 25 (3), 663-9 and RTBartus et al. , Neurological Res. 1995, 17, 249-58 demonstrated a neuroprotective effect of cal pain inhibitors in acute neurodegenerative disorders or ischemia, such as occur after a stroke. Likewise after experimental brain trauma, calpain inhibitors improved the recovery of memory deficits and neuromotor disorders (KESaatman et al. Proc. Natl. Acad. Sci. USA, 1996, 53,3428-3433). CLEdelstein 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, were able to show beneficial effects of calpain inhibitors after cardiac damage which were produced by ischemia or reperfusion. Since calpain inhibitors inhibit the release of the β-AP4 protein, a potential use as a therapeutic agent for Alzheimer's disease has been proposed (J.Higaki et al., Neuron, 1995, 14, 651-59). The release of interleukin-lα is also inhibited by calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6 (6), 597-601). Furthermore, it has been found that calpain inhibitors show cytotoxic effects on tumor cells (E.Shiba et al. 20th Meeting Int. Ass. Breast Cancer Res., Sendai Jp, 1994, 25th-28th Sept., Int.J.Oncol. 5 (Suppl.), 1994, 381).

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

Calpain inhibitors have already been described in the literature, but mostly these are either irreversible or peptide inhibitors. Irreversible inhibitors are usually alkali substances and have the disadvantage that they are irr. Organism react unselectively or are unstable. So these inhibitors often show undesirable side effects, such as toxicity, and are then restricted in use or unusable. The irreversible inhibitors include, for example, the epoxides E 64 (EBMcGowan et al., Biochem.Biophys.Res.Commun. 1989, 158, 432-5), halogen ketones (H. Angliker et al., J.Med. Cherr. 1992, 35, 216-20) or disulfides (R. Matsueda et al., Chem. Lat. 1990, 191-194).

Many known reversible inhibitors of cysteine proteases such as calpain are peptidic aldehydes, in particular dipeptide and tripepidic aldehydes such as, for example, Z-Val-Phe-H (MDL 28170) (S.Mehdi, Tends i Biol. Sci. 1991, 16, 150 -3). Under physiological conditions, peptidic aldehydes have the disadvantage that they are often instable due to the high reactivity 3 bil are, can be metabolized quickly and tend to non-specific reactions that can be the cause of toxic effects (JA Fehrentz and B. Castro, Synthesis 1983, 676-78. In JP 08183771 (CA 1996, 605307) and in EP 520336 Aldehydes which are derived from 4-piperidinoylamides and 1-carbonyl-piperidino-4-ylamides have been described as calpain inhibitors, but the aldehydes claimed here which are derived from heteroaromatically substituted amides of the general structure I have so far been described .

Peptide ketone derivatives are also inhibitors of cysteine proteases, especially calpains. For example, ketone derivatives are known as inhibitors in the case of serine proteases, the keto group being activated by an electron-withdrawing group such as CF ₃ . In the case of cysteine proteases, derivatives with ketones activated by CF ₃ or similar groups are little or ineffective (MRAngelastro et al., J.Med.Chem. 1990, 33, 11-13). Surprisingly, so far only ketone derivatives in which α-leaving groups on the one hand cause irreversible inhibition and on the other hand a carboxylic acid derivative activates the keto group have been found as effective inhibitors in calpain (see MRAngelastro et al., See above; WO 92 / 11850; WO 92,12140; WO 94/00095 and WO 95/00535). However, of these ketoamides and ketoesters, only peptide derivatives have so far been described as 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 MRAngelastro et al. ).

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

In a number of therapies such as stroke, the active ingredients are administered intravenously, for example as an infusion solution. For this purpose it is necessary to have available substances, here calpain inhibitors, which have sufficient water solubility so that an infusion solution can be prepared. However, many of the calpain inhibitors described have the disadvantage that they show little or no water solubility and are therefore not suitable for intravenous administration. Such active substances can only be applied with auxiliary substances which are intended to impart water solubility (cf. RT Bartus et al. 4

Cereb. Blood flow metab. 1994, 14, 537-544). However, these additives, for example polyethylene glycol, often have side effects or are even incompatible. A non-peptide calpain inhibitor that is therefore water-soluble without auxiliary substances would have a great advantage. Such an inhibitor has not yet been described and would therefore be new.

In the present invention, substituted non-peptidic aldehydes, ketocarboxylic acid esters and ketoamide derivatives have been described. These compounds are new and surprisingly show the possibility of incorporating rigid structural fragments into potent non-peptide inhibitors of cysteine proteases, e.g. Calpain. Furthermore, salt bonds with acids are possible with the present compounds of the general formula I, which all carry at least one aliphatic amine radical. A large number of these substances show water solubility as a 0.5% solution at pH 0 4-5 and thus they show the desired profile for intravenous application, as is required, for example, in stroke therapy.

The present invention relates to amides of the general formula I

_R ^ AA _N A ^ ^RE

3 / (CH ₂ ) _χ HO

R and its tautomeric and isomeric forms, possible enantiomeric and diastereomeric forms, as well as possible physiologically acceptable salts, in which the variables have the following meaning:

R ^{1 can} denote hydrogen, Ci-Cg-alkyl, branched and unbranched, phenyl, naphthyl, quinolinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinazolyl, quinoxalyl, thienyl, benzothienyl, benzofuranyl, furanyl, and indolyl, the rings also having can be substituted up to 3 radicals R ⁶ , and

R ^{2 is} hydrogen, Ci-C _δ alkyl, branched or unbranched, O-Ci-Cg-alkyl, branched or unbranched, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -C-C ₆ alkyl- Phenyl, C ₂ -C ₆ alkenyl phenyl, C ₂ -C ₆ alkynyl phenyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO-Cι-C ₄ -alkyl, NHCO-C ₄ alkyl, NHCO-phenyl, CONHR ⁹ , NHS0 ₂ -C-C ₄ alkyl, NHS0 ₂ -phenyl, S0 ₂ -C-C ₄ alkyl and S0 ₂ -phenyl mean and

R ^{3 can represent} NR ⁷ R ⁸ or a ring like - NN Rs -N - ^B '-N ^^ - \> - -ζ ^~ N - R »

I) n / (R) "

R ⁴ -Ci-Cε-alkyl, branched or unbranched, which can also carry a phenyl, pyridyl or naphthyl ring, which in turn is substituted with 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

\ f ^* y means and

R ^{6 is} hydrogen, Cχ-C-alkyl, branched or unbranched,

-OC ₁ -C ₄ - alkyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO -CC ₄ -alkyl, -NHCO -CC ₄ -alkyl , -NHCO-phenyl, -NHS0 ₂ -Cι-C ₄ alkyl, -NHS0 -phenyl, -S0 ₂ -Cι-C ₄ alkyl and -S0_Phenyl means and

R ^{7 is} hydrogen, Cχ-C ₆ alkyl, linear or branched, and that can be substituted with a phenyl ring, which itself can be substituted with one or two radicals R ¹⁰ , and

R ^{8 is} hydrogen, Ci-C _δ- alkyl, linear or branched, and that can be substituted with a phenyl ring, which itself can also be substituted with one or two radicals R ¹⁰ , and

R ^{9 is} hydrogen, Ci-Cβ-alkyl, branched or unbranched, which can also carry a substituent R ¹⁶ , phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, naphthyl, quinolinyl, imidazolyl, which also have one or two substituents R ¹⁴ can, and

R ¹⁰ hydrogen f, -CC ₄ alkyl, branched or unbranched,

-0--C-C ₄ alkyl, OH Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO-Cι-C ₄ alkyl, -NHCO-Cι-C ₄ alkyl , -NHCO- phenyl, -NHS0 ₂ -Cι-C ₄ alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -C _x -C alkyl and -S0 ₂ - phenyl can mean R ^{11 is} hydrogen, Ci-Cg-alkyl, linear or branched, and that can be substituted with a phenyl ring, which itself can also be substituted with one or two radicals R ¹⁰ , and

R ^{12 is} hydrogen, Ci-Cg-alkyl, branched and unbranched, means, and

• NNR ⁷ - - "-O ^'

R '

NR '- (CH ₂ ) "- N

R *

R ^{13 is} hydrogen, Ci-Cg-alkyl, branched or unbranched, that with a phenyl ring, which can still carry a radical R ¹⁰ , and with

may be substituted, and

R ^{14 is} hydrogen, Cχ-Cg-alkyl, branched or unbranched,

0-Cχ-Cg-alkyl, branched or unbranched, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO-Cι-C ₄ alkyl means or two radicals R ¹⁴ one Can represent bridge OC (R ¹⁵ ) ₂ 0 and

R ^{15 is} hydrogen, Ci-Cg-alkyl, branched and unbranched, means and

R ^{16 is} phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl,

Pyrazyl, pyrrolyl, naphthyl, quinolinyl, imidazolyl ring, which can also carry one or two substituents R ⁶ , and

A - (CH ₂ ) _m "- - (CH ₂ ) _m -0- (CH ₂ ) ₀ -, - (CH ₂ ) ₀ -S- (CH ₂ ) _m -, - (CH ₂ ) ₀ -SO- (CH ₂ ) _m -, - (CH ₂ ) ₀ -S0 ₂ - (CH ₂ ) _m -, -CH = CH-, -C≡C-, -CO-CH = CH-, - (CH ₂ ) ₀ -CO- (CH ₂ ) _m -, - (CH ₂ ) _m -NHCO- (CH ₂ ) ₀ "- (CH ₂ ) _m

- CONH- (CH ₂ ) ₀ ~. - ⁽ CH ₂ ⁾ m ^~ NHS0 ₂ - (CH ₂ ) ₀ -, -NH-CO-CH = CH-, - (CH ₂ ) _m

- S0 ₂ NH- (CH ₂ ) o - - -CH = CH-C0NH- and means

NN and

R ¹ - together too

mean and 7 B means phenyl, pyridine, pyrimidine, pyrazine, imidazole and thiazole and

x 1, 2 or 3 and

n represents a number 0, 1 or 2, and

m, o independently of one another means a number 0, 1, 2, 3 or 4.

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

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

The invention further relates to the physiologically tolerable salts of the compounds I, which can be obtained by reacting compounds I with a suitable acid or base. Suitable acids and bases are listed, for example, in Progress in Pharmaceutical Research, 1966, Birkhäuser Verlag, Vol. 10, pp. 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. or sodium hydroxide, lithium hydroxide,. Potassium hydroxide and tris.

The amides I according to the invention can be prepared in various ways, which have been outlined in the synthesis scheme.

Synthesis scheme

Heterocyclic carboxylic acids II are combined with suitable amino alcohols III to give the corresponding amides IV. Common peptide coupling methods are used, which are described in either CRLarock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972f. or in Houben-Weyl, Methods of Organic Chemistry, 4th edition, E5, Kap.V. Preferably works 8 one with "activated" acid derivatives of II, wherein the acid group COOH is converted into a group COL. L represents a leaving group such as Cl, imidazole and N-hydroxybenzotriazole. This activated acid is then reacted with amines to give the amides IV. The reaction takes place in anhydrous, inert solvents such as methylene chloride, 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 customary oxidation reactions can be used for this (see CRLarock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 f.) Such as Swern- and Swern-analogous oxidations (TTTidwell, Synthesis 1990, 857-70), sodium hypochlorite / TEMPO (S .L.Harbenson et al., See above) or Dess-Martin (J.Org.Chem. 1983, 48, 4155). It is preferred to work here in inert aprotic solvents such as dimethylformamide, tetrahydrofuran or methylene chloride with oxidizing agents such as DMSO / py x S0 ₃ or DMSO / oxalyl chloride at temperatures from -50 to + 25 ° C., depending on the method (see above literature) .

Alternatively, the carboxylic acid II can be reacted with aminohydroxamic acid derivatives VI to give benzamides VII. The same reaction procedure is used as for the preparation of IV. The hydroxam derivatives VI can be obtained from the protected amino acids V by conversion with a hydroxylamine. An amide production process already described is also used here. The protective group X, for example Boc, is split off in the customary manner, for example using trifluoroacetic acid. The amide hydroxamic acids VII thus obtained can be converted into the aldehydes I according to the invention by reduction. For example, lithium aluminum hydride is used as a reducing agent at temperatures from -60 to 0 ° C in inert solvents such as tetrahydrofuran or ether.

Analogous to the last method, carboxylic acids or acid derivatives, such as esters IX (Y = COOR ', COSR'), can also be prepared, which can likewise be converted into the aldehydes I according to the invention by reduction. These methods are listed in R.C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, pages 619-26.

The heterocyclically substituted amides I bearing a ketoamide or ketoester group according to the invention can be prepared in various ways, which were outlined in synthesis schemes 2 and 3. If appropriate, the carboxylic acid esters Ha are converted into acids II with acids or bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an aqueous medium or in mixtures of water and organic solvents such as alcohols or tetrahydrofuran at room temperature or elevated temperatures, such as 25-100 ° C.

These acids II are linked to an α-amino acid derivative using customary conditions which are described, for example, in Houben-Weyl, Methods of Organic Chemistry, 4th edition, E5, chap. V, and C.R. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, Ch. 9 are listed.

For example, the carboxylic acids II are converted into the “activated” acid derivatives Ilb = Y-COL, where L is a leaving group such as Cl, imidazole and N-hydroxybenzotriazole and then by adding an amino acid derivative H ₂ N-CH (R ³ ) -COOR converted into the derivative XI. This reaction takes place in anhydrous, inert solvents such as methylene chloride, tetrahydrofuran and dimethylformamide at temperatures from -20 to + 25 ° C.

R «

R '-A

B-CONH- ^ ^ COOR COOH

<R ² >". I

C xt C xπ

R <

Ri - A

B - CONH

R⁵

<R

R ⁵

c = RMCH) x-

The derivatives XI, which are generally esters, are converted into the ketocarboxylic acids XII analogously to the hydrolysis described above. The keto esters I 'are prepared in a Dakin-West analog reaction, using a method by ZhaoZhao Li et 10 al. J.Med.Chem., 1993, 36, 3472-80. A carboxylic acid such as XII is reacted with oxalic acid monoester chloride at elevated temperature (50-100 ° C) in solvents such as tetrahydrofuran and then the product thus obtained with bases such as sodium ethanolate in ethanol at temperatures of 25-80 ° C to the ketoester according to the invention I 'implemented. As described above, the keto esters I 'can, for example, be hydrolyzed to ketocarboxylic acids according to the invention.

The conversion to ketobenzamides I 'is also carried out analogously to the method by ZhaoZhao Li et al. (see above). The keto group in I 'is protected by adding 1,2-ethanedithiol with Lewis acid catalysis, such as, for example, boron trifluoride etherate, in inert solvents, such as methylene chloride, at room temperature, whereupon a dithiane is obtained. These derivatives are reacted with amines R3-H in polar solvents, such as alcohols, at temperatures from 0-80 ° C., the ketoamides I (R ⁴ -7. Or NR ⁷ R ⁸ ) being obtained.

Scheme 2

R '

(R ² ) "

R '- A

R <

R «(R2) _n

⁽ **>"Oxidaeon

B - CONH

B CONH

R5 ' -A

R5 R '- A -

R5 '-A

XV

C = R ³ - (CH,) _X -

An alternative method is shown in Scheme 2. The keto-carboxylic acids II are derived from aminohydroxycarboxylic acid derivatives XIII (preparation of XIII see S.L. Harenson et al., J.Med.Chem. 1994, 37,2918-29 or JP Burkhardt et al. Tetrahedron Let. 11

1988, 29, 3433-3436) using customary peptide coupling methods (see above, Houben-Weyl), whereby amides XIV are obtained. These alcohol derivatives XIV can be oxidized to the ketocarboxylic acid derivatives I according to the invention. You can do this with various common oxidation reactions (see C.R. Larock,

Comprehensive Organic Transformations, VCH Publisher, page 604 f.) Such as Swern- and Swern-analogous oxidations, preferably dimethyl sulfoxide / pyridine-sulfur trioxide complex in solvents such as methylene chloride or tetrahydrofuran, optionally with the addition of dimethyl sulfoxide, at room temperature or temperatures from -50 to 25 ° C, (TTTidwell, Synthesis 1990, 857-70) or sodium hypochlorite / TEMPO (SLHarbenson et al., see above).

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

The preparation of the carboxylic acid esters II have in some cases already been described or are carried out in accordance with customary chemical methods.

Compounds in which X is a bond are produced by conventional aromatic coupling, for example Suzuki coupling with boric acid derivatives and halides with palladium catalysis or copper-catalytic coupling of aromatic halides. The alkyl-bridged residues (X = - (CH ₂ ) m-) can be prepared by reducing the analog ketones or by alkylating the organolithium, e.g. ortho-phenyloxazolidines, or other organometallic compounds (see IMDordor, et al., J.Che Soc. Perkin Trans. I, 1984, 1247-52).

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

The sulfoxides and sulfones are accessible by oxidation of the corresponding thioethers. 12

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

The chalcones are formed by condensation from acetophenones with aldehydes and can optionally be converted into the analog alkyl derivatives by hydrogenation.

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

The dialkylaminoalkyl substituents are obtained by reductive amination of the aldehyde derivatives with the corresponding amines in the presence of borohydrides, such as BH ₃ -pyridine complex or or NaBH ₃ CN (A: F: Abdel-Magid, C: A: Maryanoff, KG Carson, Tetrahedron Lett 10990, 31, 5595; AE: Moormann, Synth. Commun. 1993, 23, 789).

The heterocyclically substituted amides I contained in the present invention are inhibitors of cysteine proteases, in particular cysteine proteases such as calpains I and II and cathepsins B and L.

The inhibitory effect of the heterocyclically substituted amides I was determined using enzyme tests customary in the literature, a concentration of the inhibitor at which 50% of the enzyme activity is inhibited being determined as the yardstick (= IC ₅₀ ). The amides I were measured in this way for the inhibitory action of calpain I, calpain II and cathepsin B.

Cathepsin B test

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

2μL of an inhibitor solution, prepared from inhibitor and DMSO (final concentrations: 100μM to 0.01μM), are added to 88μL cathepsin B (cathepsin B from human liver (Calbiochem), diluted to 5 units in 500μM buffer). This mixture is preincubated for 60 minutes at room temperature (25 ° C.) and then the reaction is started by adding 10 μL 10 mM Z-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is monitored for 30 minutes at 405nM in a microplate reader. The ICso's are then determined from the maximum gradients. 13

Calpain I and II test

The inhibitory properties of calpain inhibitors are tested in buffer with 50 mM Tris-HCl, pH 7.5; 0.1 M NaCl; 1mM dithiotreithol; 0.11 mM Ca Cl ₂ , the fluorogenic calpain substrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachern / Switzerland) being used. Human μ-calpain is isolated from erythrocytes and after several chromatographic steps (DEAE-Sepharose, Phenyl-Sepharose, Superdex 200 and Blue-Sepharose), enzyme with a purity> 95% is obtained, assessed according to SDS-PAGE, Western Blot Analysis and N -terminal sequencing. The fluorescence of the cleavage product 7-amino-4-methylcoumarin (AMC) is monitored in a Spex-Fluorolog fluorimeter at λex = 380 nm and λem = 460 nm. In a measuring range of 60 min. the cleavage of the substrate is linear and the autocatalytic activity of calpain is low if the tests are carried out at temperatures of 12 ° C.

The inhibitors and the calpain substrate are added to the test batch as DMSO solutions, the final concentration of DMSO not exceeding 2%.

In a test batch, 10 μl substrate (250μM final) and then 10 μl of μ-calpain (2μg / ml final, i.e. 18 nM) are added to a 1 ml cuvette containing buffer. The calpain-mediated cleavage of the substrate is carried out for 15-20 min. measured. Then add 10 μl inhibitor (50 - 100 μM solution in DMSO) and measure the inhibition of the cleavage for a further 40 min.

Ki values are determined using the classic equation for reversible inhibition:

(Methods in Enzymology,)

Ki = I / (vO / vi) - 1; where 1 = inhibitor concentration, vO = initial rate before adding the inhibitor; vi = equilibrium reaction rate.

The speed is calculated from v = AMC release / time i.e. Altitude / time.

Calpain is an intracellular cysteine protease. Calpain inhibitors must pass through the cell membrane to prevent the breakdown of intracellular proteins by calpain. Some known calpain inhibitors, such as E 64 and leupeptin, only poorly cross the cell membranes and accordingly, although they are good calpain inhibitors, show only poor activity on cells. The aim is to create connections with better membrane 14 common to find. We use human platelets as evidence of the passage of calpain inhibitors into the membrane.

Calpain-mediated breakdown of the tyrosine kinase pp60src in platelets

After platelet activation, the tyrosine kinase pp60src is cleaved by calpain. This was done by Oda et al. in J. Biol. Chem., 1993, Vol 268, 12603-12608. It was shown that the cleavage of pp60src can be prevented by calpeptin, an inhibitor for calpain. Based on this publication, the cellular effectiveness of our substances was tested. Fresh human blood with citrate was mixed for 15 min. centrifuged at 200g. The platelet-rich plasma was pooled and diluted 1: 1 with platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KCl, 0.5 mM MgCl ₂ × 6 H ₂ O, 0.24 mM NaH ₂ PO ₄ × H ₂ 0, 12 mM NaHC0 ₃ , 5, 6 mM glucose, 1 mM EDTA, pH 7.4). After a centrifugation and washing step with platelet buffer, the platelets were adjusted to 10 ⁷ cells / ml. The human platelets were isolated at RT.

In the test mixture, isolated platelets (2 x 10 ⁶ ) with different concentrations of inhibitors (dissolved in DMSO) for 5 min. pre-incubated at 37 ° C. The platelets were then activated with 1 μM Ionophore A23187 and 5 mM CaCl. After 5 min. Incubation, the platelets were briefly centrifuged at 13000 rpm and the pellet was taken up in SDS sample buffer (SDS sample buffer: 20 mM Tris-HCl, 5 mM EDTA, 5 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 5 μg / ml leupeptin, 10 μg / ml pepstatin, 10% glycerin and 1% SDS). The proteins were separated in a 12% gel and pp60src and its 52-kDa and 47-kDa cleavage products were identified by Western blotting. The polyclonal rabbit antibody Anti-Cys-src (pp60 ^c-src ) used was purchased from Biomol Feinchemischen (Hamburg). This primary antibody was detected using an HRP-coupled second goat antibody (Boehringer Mannheim, FRG). Western blotting was carried out according to known methods.

The cleavage of pp60src was quantified densitometrically, using controls which were not activated (control 1: no cleavage) and plates treated with ionophore and calcium (control 2: corresponds to 100% cleavage). The ED ₅ o value corresponds to the concentration of inhibitor at which the intensity of the color reaction is reduced by 50%.

Glutamate-induced cell death on cortical neurons 15

The test was carried out as in Choi D. w. , Maulucci-Gedde M.A. and Kriegstein A.R., "Glutamate neurotoxicity in cortical cell culture". J. Neurosci. 1989, 7, 357-368.

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

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

Calcium-mediated cell death in NT2 cells

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

A number of neurological diseases or mental disorders result in increased glutamate activity, which leads to states of overexcitation or toxic effects in the central nervous system (CNS). Glutamate mediates its effects via various receptors. Two of these receptors are classified according to the specific agonists NMDA receptor and AMPA receptor. Antagonists against these glutamate mediated effects 16 can thus be used to treat these diseases, in particular for therapeutic use against neurodegenerative diseases such as Huntington's chorea and Parkinson's disease, neurotoxic disorders after hypoxia, anoxia, ischemia and after lesions such as those occurring after stroke and trauma, or also as antiepileptics (see Pharmaceutical Research 1990, 40, 511-514; TIPS, 1990, 11, 334-338; Drugs of the Future 1989, 14, 1059-1071). De

Protection against cerebral overexcitation by excitatory amino acids (NMDA or AMPA antagonism in the mouse)

The intracerebral application of excitatory amino acids EAA (Excitatory Amino Acids) induces such a massive overexcitation that it leads to cramps and the death of the animals (mouse) in a short time. Through systemic, e.g. These symptoms can be inhibited intraperitoneally, administration of central active ingredients (EAA antagonists). Since the excessive activation of EAA receptors of the central nervous system plays an important role in the pathogenesis of various neurological diseases, it can be concluded from the proven EAA antagonism in vivo that the substances can be used therapeutically against such CNS diseases. An ED 50 value was determined as a measure of the effectiveness of the substances, in which 50% of the animals become symptom-free by a fixed dose of either NMDA or AMPA by the previous ip administration of the measuring substance.

The heterocyclically substituted amides I are inhibitors of cysteine derivatives such as calpain I or II and cathepsin B or L and can thus be used to combat diseases which are associated with an increased enzyme activity of the calpain enzymes or cathepsin enzymes. The present amides I can thereafter be used for the treatment of neurodegenerative diseases which occur after ischemia, trauma, subarachnoid bleeding and stroke, and of neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease, Huntington's disease and epilepsy and furthermore for the treatment of damage to the Heart after cardiac ischemia, kidney damage after renal ischemia, skeletal muscle damage, muscular dystrophy, damage caused by proliferation of smooth muscle cells, coronary vasospasm, cerebral vasospasm, cataracts of the eyes, restenosis of the bloodstream after angioplasty. In addition, the amides I can be useful in the chemotherapy of doors and their metastasis and for the treatment of diseases in which an increased level of interleukin-1 is 17 occurs, as with inflammation and rheumatic diseases.

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

For local external use, for example in powders, ointments or sprays, the active ingredients can be contained in the usual concentrations. As a rule, the active substances are contained in an amount of 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 per kg body weight are given in a single dose. The preparation can be administered daily in one or more doses depending on the type and severity of the diseases.

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

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

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

The pharmaceutical preparations can be administered in various modes of administration, for example orally, parenterally and intravenously by infusion, subcutaneously, intraperitoneally and topically. Formulations like tablets, emulsions, 18th

Infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays possible.

Examples

example 1

2- ((4-Phenylpiperazin-l-yl) methyl) benzoic acid N- (3-phenylpropan-l-al-2-yl) amide

a) Methyl 2- (4-phenylpiperazin-l-ylmethyl) benzoate

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

b) 2- (4-phenylpiperazin-l-ylmethyl) benzoic acid

16.8 g of the intermediate compound la were placed in 150 ml of THF, and 1.7 g of LiOH in 150 ml of water were added at room temperature. The cloudy solution was clarified by adding 10 ml of MeOH. The reaction mixture was stirred at room temperature for 12 h and hydrolyzed with an equimolar amount of 1 M HC1. The reaction mixture was evaporated to dryness and the residue was taken up in methanol / toluene. After removing the solvent, 15.2 g (86%) of the still salty product were obtained.

c) 2- ((4-Phenylpiperazin-l-yl) methyl) benzoic acid N- (3-phenyl-propan-l-ol-2-yl) amide

3.0 g of the intermediate lb and 3 ml of triethylamine were placed in 50 ml of DMF. 5 g of sodium sulfate were added and the mixture was stirred for 30 minutes. 1.5 g of phenylalaninol, 1.4 g of HOBT and 2.1 g of EDC were added in succession at 0 ° C. and the mixture was stirred overnight at room temperature. The reaction mixture was poured onto distilled water, made alkaline with NaHC0 ₃ , saturated with NaCl and extracted three times with 100 ml of methylene chloride. The organic phases were washed twice with water and dried over magnesium sulfate. To 19

Concentration of the solvent gave 2.5 g (59%) of the product.

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

2.3 g of the intermediate lc were placed in the presence of 2.4 g of triethylamine in 50 ml of DMSO and mixed with 2.5 g of S0 ₃ -pyridine complex. The mixture was stirred at room temperature overnight. The mixture was poured onto 250 ml of distilled water, made alkaline with NaHC0 ₃ , saturated with NaCl, extracted with 100 ml of methylene chloride and dried over magnesium sulfate. After concentrating the solvent, the residue was dissolved in THF and the hydrochloride was precipitated with HCl in dioxane. The precipitate was filtered off and washed several times with ether, with 1.9 g (71%) of the product being obtained.

1H-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 (14H), 9.3 (1H), 9.8 ( 1H) ppm.

Example 2

2- ((4-Benzylpiperazin-l-yl) methyl) benzoic acid N- (3-phenyl-propan-l-al-2-yl) amide

a) Methyl 2- ((4-benzylpiperazin-l-yl) methyl) benzoate

10.0 g of 2-chloromethylbenzoic acid methyl ester and 9.6 g of N-benzylpiperazine were dissolved in 200 ml of DMF in analogy to Example 1a

In the presence of 15 g of potassium carbonate at 100 ° C, 17.6 g (100%) of the product.

b) 2- ((4-Benzylpiperazin-l-yl) methyl) benzoic acid

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

c) 2- ((4-Benzylpiperazin-l-yl) methyl) benzoic acid N- (3-phenyl-propan-l-ol-2-yl) amide

3.0 g of the intermediate compound 2b were mixed analogously to Example 1c 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, 2.0 g (46%) of the product being obtained. 20 d) 2- ((4-Benzylpiperazin-l-yl) methyl) benzoic acid N- (3-phenyl-propan-l-al-2-yl) amide

1.5 g of the intermediate compound 2c were analogous to Example 1d in 40 ml of DMSO in the presence of 2.3 ml of triethylamine with 1.9 g

S0 ₃ -pyridine complex oxidized in 20 ml of DMSO, 0.4 g (21%) of the product being obtained in the form of the fumarate.

1H-NMR (dg-DMSO): δ = 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-l-yl) methyl) benzoic acid N- (1-carbamoyl-1-oxo-3-phenylpropan-2-yl) amide

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

1.5 g of the intermediate lb were analogous to Example lc in

40 ml DMF with 0.7 ml triethylamine, 1.0 g

3-Amino-2-hydroxy-4-phenylbutyric acid amide hydrochloride, 0.6 g

HOBT and 0.9 g EDC were added, with 0.8 g (38%) of the product being obtained.

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

0.7 g of the intermediate 3a were oxidized analogously to Example 1d in 20 ml of DMSO in the presence of 0.8 g of triethylamine with 0.7 g of S0 ₃ -pyridine complex, 0.1 g (18%) of the product being obtained in the form of the free base.

1H-NMR (d ₆ -DMSO): δ = 2.3 (4H), 2.8-3.5 (8H), 5.3 (1H), 6.7-7.5 (16H), 7.8 (1H), 8.1 (1H), 10.3 (1H) ppm.

Example 4

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

a) Methyl 2- (4- ((3-methylphenyl) piperazin-l-yl) methyl) benzoate 21

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

b) 2- (4- ((3-Methylphenyl) piperazin-l-yl) methyl) benzoic acid

5.9 g of the 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, with 2.9 g (51%) of the product being obtained.

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

1.8 g of the intermediate compound 4b were introduced analogously to Example 1c in 50 ml of DMF in the presence of 2.7 ml of triethylamine, and 0.8 g of HOBT, 1.3 g of 3-amino-2-hydroxy-4-phenylbutyric acid amide hydrochloride and 1.2 EDC were added in succession, where 1.4 g (50%) of the product was obtained.

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

1.2 g of the intermediate compound 4c were dissolved in 30 ml of DMSO analogously to Example 1d and oxidized in the presence of 1.5 ml of triethylamine with 1.6 g of SO ₃ -pyridine complex, 1.0 g (83%) of the product being obtained.

MS: m / e = 484 (M +)

Examples 5 and 6 were synthesized analogously to Example 1.

Example 5

3- ((4-Phenylpiperazin-l-yl) methyl) benzoic acid N- (3-phenyl-propan-l-al-2-yl) amide fumarate

1H-NMR (d ₆ -DMS0): δ = 2.5 (4H), 2.9 (IH), 3.2 (4H), 3.3 (IH), 3.7 (2H), 4.5 (IH), 6.6 (2H), 6.75 (IH ), 6.9 (2H), 7.2 (2H), 7.2-7.3 (5H), 7.45 (IH), 7.55 (IH), 7.75 (IH), 7.8 (2H), 8.9 (IH), 9.7 (IH) ppm. 22

Example 6

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

MS: m / e = 568 (M ⁺ +1)

Example 7

4- (N- (3,4-Dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid-N- (3-phenylpropan-l-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 placed in 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 h. After the salts had been filtered off, the mother liquor was concentrated, the residue was dissolved in ethyl acetate and washed with water. The aqueous phase was made alkaline and extracted several times with ethyl acetate, 6.6 g (32%) of the product being obtained as a white solid.

b) 4- (N- (3,4-Dioxomethylene) benzyl-N-methylaminomethyl) enoic acid N- (3-phenylpropan-l-ol-2-yl) amide

4.4 g of the intermediate compound 5a were placed in 50 ml of DMF in the presence of 2.9 ml of triethylamine analogously to Example 1c, and 1.8 g of HOBT, 2.0 g of phenylalanine and 2.8 EDC were added in succession, 2.3 g (40%) of the product being obtained.

c) 4- (N- (3,4-Dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid-N- (3-phenylpropan-l-al-2-yl) mid

2.0 g of the intermediate 5b were analogous to Example ld in

60 ml of DMSO dissolved and oxidized in the presence of 1.8 ml of triethylamine with 2.1 g of S0 ₃ -pyridine complex, 1.3 g (68%) of the product being obtained.

1H-NMR (CF ₃ COOD): δ = 2.9 (3H), 3.2 (2H), 4.3-4.9 (5H), 6.1 (2H), 6.6 (IH), 6.9 (3H), 7.2-7.4 (5H), 7.8 (2H), 8.25 (2H) ppm.

MS: m / e = 430 (M ⁺ ) 23

Examples 8-28 were prepared analogously to Example 7.

Example 8

4- (N-Benzyl-N-methylaminomethyl) benzoic acid N- (3-phenyl-propan-l-al-2-yl) amide

IH-NMR (CF ₃ COOD): δ = 2.9 (3H), 3.2 (2H), 4.3-5.0 (5H), 6.7 (IH), 7.25-7.5 (8H), 7.55 (2H), 7.8 (2H), 8.2 (2H) ppm.

MS: m / e = 386 (M ⁺ )

Example 9

4- (N- (4-Methoxy) benzyl-N-methylaminomethyl) benzoic acid N- (3-phenylpropan-l-al-2-yl) amide

IH-NMR (CF ₃ COOD): δ = 2.9 (3H), 3.3 (2H), 4.0 (3H), 4.3-4.9 (5H), 6.7 (IH), 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-l-al-2-yl) amide

IH-NMR (CF ₃ COOD): δ = 1.1 (3H), 1.6 (2H), 2.0 (2H), 2.9 (3H), 4.3-4.5 (3H), 4.7 (IH), 4.8 (IH), 6.6 ( IH), 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) enoic acid N- (3-butan-l-al-2-yl) amide

IH-NMR (CF ₃ COOD): δ = 1.1 (3H), 1.6 (2H), 1.9 (2H), 2.9 (3H), 4.25-4.6 (4H), 4.75 (IH), 6.1 (2H), 6.6 ( IH), 6.9 (3H), 7.8 (2H), 8.3 (2H) ppm.

MS: m / e = 382 (M ⁺ )

Example 12 24

4- (N- (4-Methoxy) benzyl-N-methylaminomethyl) benzoic acid N- (3-butan-l-al-2-yl) amide

MS: m / e = 368 (M ⁺ )

Example 13

4- (N- (3,4-Dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid-N- (3-cyclohexylpropan-l-al-2-yl) amide

IH-NMR (CF ₃ COOD): δ = 1.0-2.0 (13H), 2.9 (3H), 4.3-4.9 (4H), 6.1 (2H), 6.6 (IH), 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-cyclohexyl-propan-l-al-2-yl) amide

IH-NMR (dg-DMSO): δ = 1.0-1.8 (13H), 2.1 (3H), 3.4 (2H), 3.5 (2H), 4.3 (IH), 7.1-7.4 (5H), 7.5 (2H), 7.8 (2H), 8.8 (IH), 9.5 (IH) ppm.

Example 15

4- (N- (4-Methoxy) benzyl-N-methylaminomethyl) benzoic acid-N- (3-cyclohexylpropan-l-al-2-yl) amide

IH-NMR (CDC1 ₃ ): δ = 1.0-1.8 (13H), 2.1 (3H), 3.4 (2H), 3.5 (2H), 3.7 (3H), 4.3 (IH), 6.8 (2H), 7.25 (2H ), 7.5 (2H), 7.9 (2H), 8.8 (IH), 9.5 (IH) ppm.

Example 16

4- ((2-phenylpyrrolid-l-yl) methyl) benzoic acid N- (3-cyclohexylpropan-l-al-2-yl) mid

MS: m / e = 420 (M ⁺ )

Example 17

4- ((2-phenylpyrrolid-l-yl) methyl) benzoic acid N- (3-butan-l-al-2-yl) amide

MS: m / e = 364 (M ⁺ ) 25th

Example 18

4- ((2-Phenylpyrrolid-l-yl) methyl) benzoic acid N- (3-phenyl-propan-l-al-2-yl) amide

MS: m / e = 412 (M ⁺ )

Example 19

4- ((1, 2, 3, 4-Dihydroquinolin-l-yl) methyl) benzoic acid N- (3-cyclohexylpropan-l-al-2-yl) amide

IH-NMR (CDC1 ₃ ): δ = 1.0-1.9 (13H), 2.0 (2H), 2.8 (2H), 3.3 (2H), 4.5 (2H), 4.8 (IH), 6.4 (IH), 6.5 (2H ), 7.0 (2H), 7.4 (2H), 7.8 (2H), 9.7 (IH) ppm.

MS: m / e = 404 (M ⁺ )

Example 20

4- ((1, 2, 3, 4-Dihydroquinolin-l-yl) methyl) benzoic acid N- (3-phenylpropane-l-al-2-yl) amide

IH-NMR (dg-DMSO): δ = 1.9 (2H), 2.75 (2H), 2.9 (IH), 3.3 (IH), 3.4 (2H), 4.4 (IH), 4.5 (2H), 6.3 (2H) , 6.8 (2H), 7.1-7.25 (5H), 7.3 (2H), 7.7 (2H), 8.8 (IH), 9.5 (IH) ppm.

MS: m / e = 398 (M ⁺ )

Example 21

4- ((1, 2, 3, 4-Dihydroquinolin-l-yl) methyl) enzoic acid N- (3-butan-l-al-2-yl) amide

IH-NMR (d ₆ -DMSO): δ = 0.9 (3H), 1.2-2.0 (6H), 2.7 (2H), 3.3 (2H), 4.2 (IH), 4.5 (2H), 6.4 (2H), 6.8 (2H), 7.3 (2H), 7.8 (2H), 8.8 (IH), 9.5 (IH) ppm.

MS: m / e = 350 (M ⁺ )

Example 22

4- ((1,2,3, 4-Dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-cyclohexylpropan-l-al-2-yl) amide 26

IH-NMR (dg-DMSO): δ = 0.9-1.8 (13H), 2.7-2.9 (4H), 3.6 (2H), 3.75 (2H), 4.4 (IH), 6.9-7.1 (4H), 7.4 (2H ), 7.8 (2H), 8.8 (IH), 9.5 (IH) ppm.

MS: m / e = 404 (M ⁺ )

Example 23

4- ((1, 2, 3, 4-Dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-phenylpropan-l-al-2-yl) amide

IH-NMR (dg-DMSO): δ = 2.7 (2H), 2.8 (2H), 2.9 (IH), 3.2 (IH), 3.5 (2H), 3.7 (2H), 4.5 (IH), 6.9-7.1 ( 4H), 7.2-7.3 (5H), 7.5 (2H), 7.75 (2H), 8.8 (IH), 9.5 (IH) ppm.

MS: m / e = 398 (M ⁺ )

Example 24

4- ((1, 2, 3, 4-Dihydroisoquinolin-2-yl) methyl) benzoic acid-N- (3-butan-l-al-2-yl) amide hydrochloride

IH-NMR (dg-DMSO): δ = 0.9 (3H), 1.2-2.0 (4H), 3.0 (IH), 3.3 (2H), 3.6 (IH), 4.1-4.6 (5H), 7.2 (4H), 7.8 (2H), 8.0 (2H), 9.0 (IH), 9.5 (IH), 11.75 (IH) ppm.

Example 25

4- ((6, 7-Dimethoxy-l, 2,3, 4-dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-cyclohexylpropan-l-al-2-yl) amide

IH-NMR (dg-DMSO): δ = 0.9-1.9 (13H), 2.7 (4H), 3.4 (2H), 3.6 (3H), 3.65 (2H), 3.7 (3H), 4.3 (IH), 6.5 ( IH), 6.6 (IH), 7.5 (2H), 7.8 (2H), 8.8 (IH), 9.5 (IH) ppm.

MS: m / e = 464 (M ⁺ )

Example 26

4- ((6, 7-Dimethoxy-l, 2,3, 4-dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-phenylpropan-l-al-2-yl) amide

IH-NMR (dg-DMSO): δ = 2.7 (4H), 2.9 (IH), 3.25 (IH), 3.6 (6H), 3.7 (2H), 4.5 (IH), 6.6 (IH), 6.7 (IH) , 7.2-7.3 (5H), 7.4 (2H), 7.8 (2H), 8.9 (IH), 9.6 (IH) ppm. 27

MS: m / e = 458 (M ⁺ )

Example 27

4- ((6, 7-Dimethoxy-l, 2,3, 4-dihydroisoquinolin-2-yl) methyl) benzoic acid N- (3-butan-l-al-2-yl) amide

IH-NMR (dg-DMSO): δ = 0.9 (3H), 1.4 (2H), 1.5-1.8 (2H), 2.7 (4H), 3.4 (2H), 3.7 (3H), 3.75 (3H), 3.8 ( 2H), 4.3 (IH), 6.6 (IH), 6.7 (IH), 7.4 (2H), 7.8 (2H), 8.8 (IH), 9.5 (IH) ppm.

MS: m / e = 410 (M ⁺ )

Example 28

2- ((1, 2, 3, 4-Dihydroquinolin-l-yl) methyl) benzoic acid N- (3-butan-l-al-2-yl) amide

MS: m / e = 441 (M ⁺ )

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Claims

 89 claims 1. Amides of the general formula I (R ² ) ° f ⁴ c ^ b o 0 and their tautomeric and isomeric forms, possible enantiomeric and diastereomeric forms, as well as possible physiologically compatible salts, in which the variables have the following meaning: 5 R ^{1 is} hydrogen, Ci-Cg-alkyl, branched and unbranched, phenyl, naphthyl, quinolinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinazolyl, quinoxalyl, thienyl, benzothienyl, benzofuranyl, furanyl, and indolyl may mean 0, the rings still can be substituted with up to 3 radicals R ⁶ , and R ^{2 is} hydrogen, C ₁ -C ₆ -alkyl, branched or unbranched, 0 -C ₁ -C ₆ -alkyl, branched or unbranched, C ₂ -C ₆ -alkenyl, 5 C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkylphenyl, C ₂ -C ₆ -alkenylphenyl, C ₂ -C ₆ alkynylphenyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO -CC-C ₄ alkyl, NHCO -CC-C ₄ alkyl , NHCO-phenyl, CONHR ⁹ , NHS0 ₂ -Cι-C ₄ alkyl, NHS0 ₂ -phenyl, S0 ₂ -Cι-C ₄ alkyl and S0 ₂ -phenyl mean and 30 R ^{3 can represent} NR ⁷ R ⁸ or a ring like -, _ ^" ^ R '- f ^ S 35

-

I <">" \ R ^β ) / 40 R ⁴ -C-C ₆ alkyl, branched or unbranched, which can also carry a phenyl, pyridyl, thienyl, cyclohexyl, indolyl or naphthyl ring, which in turn is substituted with a maximum of two R ⁶ radicals, and 45 302/98 Dp / AS 90 R ^{5 is} hydrogen f, COOR ¹¹ and CO-Z, wherein Z is NR ¹² R ¹³ and R? -rT \ -J - ". - ^• \ ^ r -" ^ _> means and R ^{6 is} hydrogen, -CC-alkyl, branched or unbranched, -0-Cχ-C ₄ - alkyl, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO -CC ₄ alkyl, -NHCO-C ₁ -C-alkyl, -NHCO-phenyl, -NHS0 ₂ -C ₁ -C-alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -Cι-C ₄ -alkyl and - S0 ₂ _phenyl means and R ^{7 is} hydrogen, -CC ₆ alkyl, linear or branched, and that can be substituted with a phenyl ring, which can itself be substituted with one or two radicals R ¹⁰ , and R ^{8 is} hydrogen, Ci-C _ß- alkyl, rectilinear or branched, and that can be substituted with a phenyl ring, which itself can be substituted with one or two radicals R ¹⁰ , and R ^{9 is} hydrogen, Ci-C _ß- alkyl, branched or unbranched, which can also carry a substituent R ¹⁶ , phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, naphthyl, quinolinyl, imidazolyl, which also has one or two substituents R ¹⁴ can wear, and R ^{10 is} hydrogen, C 1 -C ₄ -alkyl, branched or unbranched, -0-C _x -C-alkyl, OH Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO -CC ₄ -alkyl, -NHCO -CC-C-alkyl, -NHCO-phenyl, -NHS0 ₂ -Cι-C-alkyl, -NHS0 ₂ -phenyl, -S0 ₂ -Cι ~ C-alkyl and -S0 ₂ -phenyl can mean R ¹¹ signifies hydrogen, Ci-Cε-alkyl, linear or branched, and which can be substituted with a phenyl ring which can itself be substituted with one or two R ¹⁰ radicals, and R ^{12 is} hydrogen, Ci-Cg-alkyl, branched and unbranched, means, and 91 NNR ' _N ^/ Jl- R ⁷ . N - ""'_; N -J— ^R? R 'N i3 hydrogen, Ci-Cg --Akkyl- (CH ₂ ) o- R ⁸ R, branched or unbranched, that with a phenyl ring, which can still carry a radical R ¹⁰ , and with may be substituted, and R ^{14 is} hydrogen, Cχ-Cg-alkyl, branched or unbranched, O-Ci-Cg-alkyl, branched or unbranched, OH, Cl, F, Br, J, CF ₃ , N0 ₂ , NH ₂ , CN, COOH, COO -CC-C ₄ alkyl means or two radicals R ¹⁴ one Can represent bridge OC (R ¹⁵ ) ₂ <and R ^{15 is} hydrogen, Ci-Cg-alkyl, branched and unbranched, means and R ^{16 is} phenyl, pyridyl, pyrimidyl, pyridazyl, Pyrazinyl, pyrazyl, pyrrolyl, naphthyl, quinolinyl, imidazolyl ring, which can also carry one or two substituents R ⁶ , and A - (CH ₂ ) _m -, - (CH ₂ ) _m -0- (CH ₂ ) ₀ -, - (CH ₂ ) ₀ -S- (CH ₂ ) _m -, - (CH ₂ ) ₀ -SO- (CH ₂ ) _m -, - (CH ₂ ) ₀ -S0 ₂ - (CH ₂ ) m -, -CH = CH-, -C≡C-, -CO-CH = CH-, - (CH ₂ ) ₀ -CO- (CH ₂ ) m -, - (CH ₂ ) _m -NHCO- (CH ₂ ) ₀ -, - (CH ₂ ) _m - CONH- (CH ₂ ) ₀ "- - (H ₂ ) m -NHS0 ₂ - (CH ₂ ) ₀ -, -NH- CO-CH = CH -, - (CH ₂ ) m - S0 ₂ NH- (CH ₂ ) ₀ -, -CH = CH-CONH- and means R ⁶ ) "0 R ⁶ )" 0 o // (R ⁶ ) o. 0 \ (R ⁶ ) "π N 0, t 0. ti H - bo H

R ^x -A together too mean and B is phenyl, pyridine, pyrimidine, pyrazine, imidazole and thiazole and x 1, 2 or 3 and n represents a number 0, 1 or 2, and 92 m, o independently of one another means a number 0, 1, 2, 3 or 4. 2. Heterocyclically substituted amides of formula I according to claim 1, wherein B pyridine or phenyl and R ^{5 is} hydrogen and R ^{9 is} hydrogen, Ci-Cg-alkyl, branched or unbranched, which still carry a substituent R ¹⁶ R ¹⁶ phenyl, which can also carry one or two substituents R ¹⁴ , and n 0 and 1 and x 1. 3. Heterocyclically substituted amides of formula I according to claim 1, wherein B pyridine or phenyl and R ⁵ CONR ¹² R ¹³ means and R ^{9 is} hydrogen, Ci-Cg-alkyl, branched or unbranched, which still carry a substituent R ¹⁶ R ¹⁶ phenyl, which can also carry one or two substituents R ¹⁴ , and n 0 and 1 and Heterocyclically substituted amides of the formula I according to claim 1, wherein B pyridine or phenyl and R ^{2 is} hydrogen R ^{5 is} hydrogen and 93 R ^{9 is} hydrogen, Ci-Cg-alkyl, branched or unbranched, which still carry a substituent R ¹⁶ R ¹⁶ phenyl, which can carry one or two substituents R ¹⁴ I, and n 0 and 1 and x 1. 5. Heterocyclically substituted amides of formula I according to claim 1, wherein B pyridine or phenyl and R ^{2 is} hydrogen R ⁵ CONR ¹² R ¹³ means and R ^{9 is} hydrogen, Ci-Cg-alkyl, branched or unbranched, which still carry a substituent R ¹⁶ R ¹⁶ phenyl, which can also carry one or two substituents R ¹⁴ , and n 0 and 1 and x 1. 6. Heterocyclically substituted amides of formula I according to claim 1, wherein A "(CH ₂ ) _m -, - (CH ₂ ) _m -0- (CH ₂ ) ₀ -, - (CH ₂ ) ₀ -S- (CH ₂ ) _m -, -CH = CH-, -C≡ C-, - (CH ₂ ) _m - CONH- (CH ₂ ) ₀ -, - (CH ₂ ) _m - S0 ₂ NH- (CH ₂ ) _o - and B pyridine or phenyl and R ^{2 is} hydrogen and R ^{5 is} hydrogen and R ^{9 is} hydrogen, Ci-Cg-alkyl, branched or unbranched, which can also carry a substituent R ¹⁶ , and R ¹⁶ phenyl and 94 m, n, o 0 and 1 and x 1. 7. heterocyclically substituted amides of the formula I according to claim 1, wherein A - (CH ₂ ) _m -, - (CH ₂ ) _m -0- (CH ₂ ) ₀ -, "(CH ₂ ) ₀ -S- (CH ₂ ) _m -, -CH = CH-, -C≡ C-, - (CH ₂ ) _m - CONH- (CH ₂ ) ₀ -, - (CH ₂ ) _m - S0 ₂ NH- (CH ₂ ) ₀ - means and B pyridine or phenyl and R ^{2 is} hydrogen R ⁵ CONR ¹² R ¹³ means and R ^{9 is} hydrogen, Ci-Cg-alkyl, branched or unbranched, which can also carry a substituent R ¹⁶ , and R16 phenyl and m, n, o 0 and 1 and x 1. 8. Heterocyclically substituted amides of formula I according to claim 1, wherein B pyridine or phenyl and R ^ R ^{2 is} hydrogen and R ^{5 is} hydrogen and R ^{9 is} hydrogen, Ci-Cg-alkyl, branched or unbranched, which can also carry a substituent R ¹⁶ , and R1 ⁶ phenyl and m, n, o 0 and 95 9. heterocyclically substituted amides of the formula I according to claim 1, wherein B pyridine or phenyl and 5 R ^ R ^{2 is} hydrogen R5 means C0NR ¹² R ¹³ and 10 R ⁹ hydrogen, Ci-Cg-alkyl, branched or unbranched, which can also carry a substituent R ¹⁶ , and R ¹⁶ phenyl and 15 m, n, o 0 x 1. 10. Use of amides of the formula I according to claims 1-5 for the treatment of diseases. 11. Use of amides of the formula I according to claims 1-5 as inhibitors of cysteine proteases. 25 12. Use according to claim 6 as inhibitors of cysteine proteases such as calpaine and cathepsine, in particular calpaine I and II and cathepsine B and L. 13. Use of amides of the formula I according to claims 1-5 for the preparation as a medicament for the treatment of diseases in which increased calpain activities occur. 14. Use of the amides of formula I according to claims 1-5 for the manufacture of medicaments for the treatment of neuro- 35 degenerative diseases and neuronal damage. 15. Use according to claim 9 for the treatment of such neurodegenerative diseases and neuronal damage caused by ischemia, trauma or mass bleeding. 40 16. Use according to claim 10 for the treatment of stroke and traumatic brain injury. 17. Use according to claim 10 for the treatment of Alzheimer's disease and Huntington's disease. 96 18. Use according to claim 10 for the treatment of epilepsy. 19. Use of the compounds of formula I according to claims 1-5 for the manufacture of medicaments and treatment of 5 damage to the heart after cardiac ischemia, damage to the kidneys after renal ischemia, skeletal muscle damage, muscular dystrophies, damage caused by proliferation of smooth muscle cells, coronary vasospasm, cerebral vasospasm, cataracts of the eyes and 10 restenosis of the bloodstream after angioplasty. 20. Use of the amides of formula I according to claims 1-5 for the manufacture of medicaments for the treatment of tumors and their metastasis. 15 21. Use of the amides of the formula I according to claims 1-5 for the manufacture of medicaments for the treatment of diseases in which increased interleukin-1 levels occur. 22. Use of the amides according to claims 1-5 for the treatment of immunological diseases such as inflammation and rheumatic diseases. 23. Pharmaceutical preparations for oral, parenteral and intraperitoneal use, containing per single dose, in addition to the usual pharmaceutical excipients, at least one amide I according to claims 1-5. 30 35 40 45