AU3818799A

AU3818799A - Novel heterocyclically substituted amides with cysteine protease-inhibiting effect

Info

Publication number: AU3818799A
Application number: AU38187/99A
Authority: AU
Inventors: Monika Knopp; Wilfried Lubisch; Achim Moller; Hans-Jorg Treiber
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1998-04-20
Filing date: 1999-04-19
Publication date: 1999-11-08
Also published as: ZA200006714B; KR20010042839A; WO1999054320A1; BG104885A; CN1306526A; PL343551A1; SK15062000A3; EP1080083A1; CA2328720A1; IL138999A0; NO20005261L; HRP20000788A2; BR9909819A; TR200003071T2; NO20005261D0; JP2002512240A; HUP0101839A3; ID26728A; HUP0101839A2

Description

0050/48969 Novel aides with heterocyclic substituents, their preparation and use The present invention relates to novel amides which are 5 inhibitors of enzymes, especially cysteine proteases such as calpain (= calcium dependant cysteine proteases) and its isoenzymes and cathepsins, for example B and L. 10 Calpains are intracellular proteolytic enzymes from the group of cysteine proteases and are found in many cells. Calpains are activated by an increase in the calcium concentration, a distinction being made between calpain I or p-calpain, which is activated by p-molar 15 concentrations of calcium ions, and calpain II or m-calpain, which is activated by m-molar concentrations of calcium ions (P. Johnson, Int. J. Biochem. 1990, 22 (8) , 811-22) . Further calpain isoenzymes have now been postulated too (K. Suzuki et al., Biol. Chem. 20 Hoppe-Seyler, 1995, 376(9), 523-9). It is suspected that calpains play an important part in various physiological processes. These include cleavages of regulatory proteins such as protein kinase 25 C, cytoskeletal 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 which are listed in M.J. Barrett et al., Life Sci. 30 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 35 the heart (e.g. myocardial infarct), of the kidney or of the central nervous system (e.g. stroke), inflammations, muscular dystrophies, cataracts of the eyes, injuries to the central nervous system (e.g. trauma), Alzheimer's disease etc. (see K.K. Wang, 0050/48969 - 2 above). It is suspected that there is a connection between these disorders and elevated and persistent intracellular calcium levels. This results in overactivation of calcium-dependent processes, which 5 are then no longer subject to physiological control. Accordingly, overactivation of calpains may also induce pathophysiological processes. It has therefore been postulated that inhibitors of 10 calpain enzymes may be useful for treating these disorders. Various investigations have confirmed this. Thus, 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 a neuroprotective effect of 15 calpain inhibitors in acute neurodegenerative disorders or ischemias like those occurring after a stroke. Likewise, calpain inhibitors improved the recovery of the memory deficits and neuromotor disturbances occurring after experimental brain trauma (K.E. Saatman 20 et al. Proc. Natl. Acad. Sci. USA, 1996, 93, 3428 3433). C.L. Edelstein et al., Proc. Natl. Acad. Sci. USA, 1995, 92, 7662-6, found a protective effect of calpain inhibitors on kidneys damaged by hypoxia. Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59(1), 25 40-8, were able to show beneficial effects of calpain inhibitors after cardiac damage produced by ischemia or reperfusion. Since the release of the @-AP4 protein is inhibited by calpain inhibitors, a potential therapeutic use for Alzheimer's disease has been 30 proposed (J. Higaki et al., Neuron, 1995, 14, 651-59). The release of interleukin-laL is likewise inhibited by calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6(6), 597-601). It has further been found that calpain inhibitors have cytotoxic effects on tumor cells 35 (E. Shiba et al. 20th Meeting Int. Ass. Breast Cancer Res., Sendai Jp, 1994, 25-28 Sept., Int. J. Oncol. 5 (Suppl.), 1994, 381).

0050/48969 - 3 Further possible uses of calpain inhibitors are detailed in K.K. Wang, Trends in Pharmacol. Sci., 1994, 15, 412-8. 5 Calpain inhibitors have already been described in the literature. However, these are predominantly either irreversible or peptide inhibitors. Irreversible inhibitors are usually alkylating substances and have the disadvantage that they react nonselectively or are 10 unstable in the body. Thus, these inhibitors often show unwanted side effects such as toxicity, and are accordingly of limited use or unusable. The irreversible inhibitors can be said to include, for example, the epoxides E 64 (E.B. McGowan et al., 15 Biochem. Biophys. Res. Commun. 1989, 158, 432-5), a halo ketones (H. Angliker et al., J. Med. Chem. 1992, 35, 216-20) or disulfides (R. Matsueda et al., Chem. Lett. 1990, 191-194). 20 Many known reversible inhibitors of cysteine proteases such as calpain are peptide aldehydes, in particular dipeptide and tripepide [sic] aldehydes such as, for example, Z-Val-Phe-H (MDL 28170) (S. Mehdi, Tends [sic] in Biol. Sci. 1991, 16, 150-3) . Under physiological 25 conditions, peptide aldehydes have the disadvantage that, owing to the high reactivity, they are often unstable, may be rapidly metabolized and are prone to nonspecific reactions which may cause toxic effects (J.A. Fehrentz and B. Castro, Synthesis 1983, 676-78. 30 JP 08183771 (CA 1996, 605307) and EP 520336 have described aldehydes derived from 4-piperidinoylamides [sic] and 1-carbonylpiperidino-4-ylamides [sic] as calpain inhibitors. However, the aldehydes which are claimed herein and are derived from amides of the 35 general structure I with heteroaromatic substituents have not previously been described. Peptide ketone derivatives are likewise inhibitors of cysteine proteases, in particular calpains. Thus, for 0050/48969 - 4 example, ketone derivatives where the keto group is activated by an electron-attracting group such as CF 3 are known to be inhibitors of serine proteases. In the case of cysteine proteases, derivatives with ketones 5 activated by CF 3 or similar groups have little or no activity (M.R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13). Surprisingly, to date only ketone derivatives in which, on the one hand, leaving groups in the a position cause irreversible inhibition and, on 10 the other hand, the keto group is activated by a carboxylic acid derivative have been found to be effective inhibitors of calpain (see M.R. Angelastro et al., see above; WO 92/11850; WO 92,12140; WO 94/00095 and WO 95/00535). However, only peptide derivatives of 15 these keto amides and keto esters have 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 M.R. Angelastro et al.). 20 Ketobenzamides have already been described in the literature. Thus, the keto ester PhCO-Abu-COOCH 2

CH

3 has been described in WO 91/09801, WO 94/00095 and 92/11850. The analogous phenyl derivative Ph-CONH-CH(CH 2 Ph)-CO-COCOOCH 3 was, however, found to be 25 only a weak calpain inhibitor in M.R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13. This derivative is also described in J.P. Burkhardt, Tetrahedron Lett., 1988, 3433-36. The significance of the substituted benzamides has, however, never been investigated to 30 date. In a number of therapies, such as [lacuna] stroke, the active ingredients are administered intravenously, for example as infusion solution. To do this it is 35 necessary to have available substances, in this case calpain inhibitors, which have adequate solubility in water so that an infusion solution can be prepared. Many of the described calpain inhibitors have, however, the disadvantage that they have only low or no 0050/48969 - 5 solubility in water and thus are unsuitable for intravenous administration. Active ingredients of this type can be administered only with ancillary substances intended to confer solubility in water (cf. R.T. Bartus 5 et al. J. Cereb. Blood Flow Metab. 1994, 14, 537-544). These ancillary substances, for example polyethylene glycol, often have side effects, however, or are even incompatible. A non-peptide calpain inhibitor which is soluble in water without ancillary substances would 10 thus be a great advantage. No such inhibitor has been described to date, and it would thus be novel. Substituted non-peptide aldehydes, keto carboxylic esters and keto amide derivatives were described in the 15 present invention. These compounds are novel and surprisingly show the possibility of obtaining potent non-peptide inhibitors of cysteine proteases, such as, for example, calpain, by incorporating rigid structural fragments. In addition, all the present compounds of 20 the general formula I have at least one aliphatic amine radical and are thus able to bind [sic] salts with acids. A large number of these substances are soluble in water in a 0.5% strength solution at pH 0.4-5 and thus the show the required profile for intravenous 25 administration as is necessary, for example, for stroke therapy. The present invention relates to amides of the general formula I 30 (R)2 R R

R

1 ..-- A R3(CH2)XH 0 and their tautomeric and isomeric forms, possible enantiomeric and diastereomeric forms, and possible 35 physiologically tolerated salts, in which the variables 0050/48969 - 6 have the following meanings: RI can be hydrogen, Ci-C 6 -alkyl, branched and unbranched, phenyl, naphthyl, quinolyl, pyridyl, 5 pyrimidyl, pyrazyl, pyridazyl, quinazolyl, quinoxalyl, thienyl, benzothienyl, benzofuranyl, furanyl and indolyl, it being possible for the rings also to be substituted by up to 3 R 6 radicals, and 10 R 2 are hydrogen, Ci-C 6 -alkyl, branched or unbranched, O-Ci-C 6 -alkyl, branched or unbranched,

C

2 -C-alkenyl, C 2

-C

6 -alkynyl, Ci-C-alkyl-phenyl,

C

2 -C-alkenyl-phenyl,

C

2 -C-alkynyl-phenyl, OH, Cl, 15 F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO-Ci-C 4 -alkyl, NHCO-Ci-C 4 -alkyl, NHCO-phenyl, CONHR 9 ,

NHSO

2 -Ci-C 4 -alkyl, NHSO 2 -phenyl, SO 2 -Ci-C 4 -alkyl and

SO

2 -phenyl, and 20 R3 can be NR7R or a ring such as -N N-e. - N2 .D -N O- . -- N -Re -N-N .) -- N (R ), Re) (R).

R

4 is -Ci-C 6 -alkyl, branched or unbranched, which may 25 also carry a phenyl, pyridyl or naphthyl ring which is in turn substituted by a maximum of two

R

6 radicals, and R is hydrogen, COOR" and CO-Z in which Z is NR 12R3 30 and -N N-- -- - Na \-j - and 0050/48969 - 7 R6 is hydrogen, Ci-C 4 -alkyl, branched or unbranched, -O-Ci-C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO-Ci-C 4 -alkyl, -NHCO-Ci-C 4 -alkyl, -NHCO-phenyl, -NHSO 2

-C-C

4 -alkyl, -NHSO 2 -phenyl, 5 -S0 2 -Ci-C 4 -alkyl and -S0 2 -phenyl, and R 7 is hydrogen, Ci-C 6 -alkyl, linear or branched, and which may be substituted by a phenyl ring which itself may also be substituted by one or two Rio 10 radicals, and R is hydrogen, Ci-C 6 -alkyl, linear or branched, which may be substituted by a phenyl ring which may itself also be substituted by one or two Rio 15 radicals, and

R

9 is hydrogen, Ci-C 6 -alkyl, branched or unbranched, which may also carry a substituent R 1 , or phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, 20 naphthyl, quinolyl, imidazolyl, which may also carry one or two substituents R 14 , and Ri 0 can be hydrogen, Ci-C 4 -alkyl, branched or unbranched, -O-Ci-C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , 25 NO 2 , NH 2 , CN, COOH, COO-Ci-C 4 -alkyl, -NHCO-Ci-C 4 -alkyl, -NHCO-phenyl, -NHSO 2 -Ci-C 4 -alkyl,

-NHSO

2 -phenyl, -S0 2

-C

1

-C

4 -alkyl and -S0 2 -phenyl Ri is hydrogen, Ci-C 6 -alkyl, linear or branched, and 30 which may be substituted by a phenyl ring which may itself also be substituted by one or two Rio radicals, and R12 is hydrogen, C 1

-C

6 -alkyl, branched and unbranched, 35 and 0050/48969 - 8 -- N N-R' -N R' -; -- N -N o . N-R7 -(CH,) -N [sic] R 1 is hydrogen, Ci-C 6 -alkyl, branched or unbranched, which may also be substituted by a phenyl ring 5 which may also carry an R 10 radical, and by [lacuna] and R 14 is hydrogen, Ci-C 6 -alkyl, branched or unbranched, 10 O-Ci-C 6 -alkyl, branched or unbranched, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO-Ci-C 4 -alkyl, or two R1 4 radicals may represent a bridge OC(Ris) 2 0, and 15 R 15 is hydrogen, Ci-C 6 -alkyl, branched and unbranched, and R16 can be a phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, pyrrolyl, naphthyl, quinolyl, 20 imidazolyl ring, which may also carry one or two substituents R 6 , and A is -(CH 2 )m-, -(CH 2 )m-0-(CH 2 )o-, -(CH 2 )o-S-(CH 2 )m-,

-(CH

2 )o-SO-(CH 2 )m-, -(CH 2 )o-SO 2

-(CH

2 )m-, -CH=CH-, 25 -C=C-, -CO-CH=CH-, - (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 - (CH 2 ) o-, -NH-CO-CH=CH-, - (CH 2 )m-SO 2 NH- (CH 2 )o-, -CH=CH-CONH- and R). 0 oR) N NtX and 0 O H 0050/48969 - 9 049 [sic] RI-A together are also [lacuna] and 5 B is phenyl, pyridine, pyrimidine, pyrazine, imidazole and thiazole and x is 1, 2 or 3, and 10 n is a number 0, 1 or 2, and m, o is, independently of one another, a number 0, 1, 2, 3 or 4. 15 The compounds of the formula I can be employed as racemates, as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are required, these can be obtained, for example, by 20 carrying out a classical racemate 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 likewise be prepared by using commercially purchasable compounds, 25 for example optically active amino acids such as phenylalanine, tryptophan and tyrosine. The invention also relates to compounds which are mesomers or tautomers of compounds of the formula I, 30 for example those in which the aldehyde or keto group in formula I is in the form of an enol tautomer. The invention further relates to the physiologically tolerated salts of the compounds I which can be 35 obtained by reacting compounds I with a suitable acid 0050/48969 - 10 or base. Suitable acids and bases are listed, for example, in Fortschritte der Arzneimittelforschung, 1966, Birkhduser Verlag, Vol. 10, pp. 224-285. These include, for example, hydrochloric acid, citric acid, 5 tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid etc., and sodium hydroxide, lithium hydroxide, potassium hydroxide and tris. The amides I according to the invention can be prepared 10 in various ways which has [sic] been outlined in the synthesis scheme. Synthesis scheme Heterocyclic carboxylic acids II are linked to suitable 15 amino alcohols III to give the corresponding amides IV. Conventional peptide coupling methods are used for this, as detailed either in C.R. [sic] Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972 et seq., or in Houben-Weyl, Methoden der 20 organischen Chemie, 4th edition, E5, Chapter V. It is preferred to use "activated" acid derivatives of II, with the acid group COOH being converted into a group COL. L is a leaving group such as, for example, Cl, imidazole and N-hydroxybenzotriazole. This activated 25 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 0 C. 30 These alcohol derivatives IV can be oxidized to the aldehyde derivatives I according to the invention. Various conventional oxidation reactions can be used for this (see C.R. [sic] Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 et seq.) 35 such as, for example, Swern and Swern-analogous oxidations (T.T. Tidwell, Synthesis, 1990, 857-70), sodium hypochloride [sic]/TEMPO (S.L. Harbenson et al., see above) or Dess-Martin (J. Org. Chem. 1983, 48, 4155). Preferably used for this are inert aprotic 0050/48969 - 11 solvents such as dimethylformamide, tetrahydrofuran or methylene chloride with oxidizing agents such as DMSO/py x SO 3 or DMSO/oxalyl chloride at temperatures from -50 to +25 0 C, depending on the method (see above 5 literature). Alternatively, the carboxylic acid II can be reacted with amino hydroxamic acid derivatives VI to give benzamides VII. The reaction in this case is carried 10 out in the same way as for preparing IV. The hydroxamic derivatives VI can be obtained from the protected amino acids V by reaction with a hydroxylamine. An amide preparation process already described is also used in this case. Elimination of the protective group X, for 15 example Boc, takes place in a normal way, for example with trifluoroacetic acid. The amide hydroxamic acids VII obtained in this way can be converted by reduction into the aldehydes I according to the invention. The reducing agent used for this is, for example, lithium 20 aluminum hydride at temperatures from -60 to OOC in inert solvents such as tetrahydrofuran or ether. Carboxylic acids or acid derivatives such as esters IX (P = COOR', COSR') can also be prepared in analogy to 25 the last process and can likewise be converted by reduction into the aldehydes I according to the invention. These processes are listed in R.C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, pages 619-26. 30 The amides I according to the invention, which have heterocyclic substituents and have a keto amide or keto ester group, can be prepared in various ways which have been outlined in synthesis schemes 2 and 3. 35 The carboxylic esters IIa are converted, where appropriate, with acids or bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide in aqueous medium or in mixtures of water and organic 0050/48969 - 12 solvents such as alcohols or tetrahydrofuran at room temperature or elevated temperatures, such as 25-100 0 C, into the acids II. 5 These acids II are linked to an a-amino acid derivative using customary conditions which are listed, for example, in Houben-Weyl, Methoden der organischen Chemie, 4th edition, E5, Chapter V, and C.R. [sic] Larock, Comprehensive Organic Transformations, VCH 10 Publisher, 1989, Ch. 9. For example, the carboxylic acids II are converted into the "activated" acid derivatives IIb = Y-COL, where L is a leaving group such as Cl, imidazole and 15 N-hydroxybenzotriazole, and then converted into the derivative XI by adding an amino acid derivative

H

2

N-CH(R

3 )-COOR. This reaction takes place in anhydrous inert solvents such as methylene chloride, tetrahydrofuran and dimethylformamide at temperatures 20 from -20 to +25 0 C. Scheme 1 R'-A OR' R'-A OH B B - C C a R4 R4 R1-A RI-A B - cONH COOR B -ONH COOH (R "CRX B - 2 ) CO' (R) C XI R4 R R( B - CONH R-OA B - CONH C C' C = Ra-(CH2)x- 0050/48969 - 13 The derivatives XI, which are usually esters, are converted into the keto carboxylic acids XII by hydrolysis analogous to that described above. The keto esters I' are prepared in a Dakin-West-analogous 5 reaction using a method of ZhaoZhao Li et al., J. Med. Chem., 1993, 36, 3472-80. This entails a [sic] carboxylic acids such as XII being reacted with oxalic monoester chloride at elevated temperature (50-100 0 C) in solvents such as, for example, tetrahydrofuran, and 10 the product obtained in this way then being reacted with bases such as sodium ethanolate in ethanol at temperatures of 25-80 0 C to give the keto ester I' according to the invention. The keto esters I' can be hydrolyzed as described above for example to keto 15 carboxylic acids according to the invention. The reaction to give keto benzamides I' likewise takes place in analogy to the method of ZhaoZhao Li et al. (see above). The keto group in I' is protected by 20 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, resulting in a dithiane. These derivatives are reacted with amines R 3 -H in polar solvents such as 25 alcohols at temperatures of 0-80 0 C, resulting in the keto amides I (R 4 = Z or NR 7

R

8

).

0050/48969 - 14 Scheme 2 c ox)0 +( W ) B - C O N C o x OH R'.ACO C x H C II )MI XIV (X - W-ly) (R2R B -coNH1 COOH (X=k') R1 - A /0 0 laa -OON B - CONH( B - CONH R & RI- .- ' O k ,sR

'

I 0c C xv C = R - (CH 2 )x 5 An alternative method is depicted in scheme 2. The keto carboxylic acids II are reacted with amino hydroxy carboxylic acid derivatives XIII (for preparation of XIII, see S.L. Harbenson et al., J. Med. Chem. 1994, 37, 2918-29 or J.P. Burkhardt et al. Tetrahedron Lett. 10 1988, 29, 3433-3436) using customary peptide coupling methods (see above, Houben-Weyl), resulting in amides XIV. These alcohol derivatives XIV can be oxidized to the keto carboxylic acid derivatives I according to the invention. It is possible to use for this various 15 customary oxidation reactions (see C.R. [sic] Larock, Comprehensive Organic Transformations, VCH Publisher, [lacuna] page 604 et seq.) such as, for example, Swern and Swern-analogous oxidations, preferably dimethyl sulfoxide/pyridine-sulfur trioxide complex in solvents 20 such as methylene chloride or tetrahydrofuran, where appropriate with the addition of dimethyl sulfoxide, at room temperature or temperatures from -50 to 25 0 C (T.T. Tidwell, Synthesis 1990, 857-70) or sodium 0050/48969 - 15 hypochloride [sic]/TEMPO (S.L. Harbenson et al., see above). In the case of a-hydroxy esters XIV (X = O-alkyl), 5 these can be hydrolyzed to carboxylic acids XV using methods analogous to those above, but preferably using lithium hydroxide in water/tetrahydrofuran mixtures at room temperature. Other esters or amides XVI are prepared by reaction with alcohols or amines under 10 coupling conditions described above. The alcohol derivative XVI can be oxidized to give keto carboxylic acid derivatives I according to the invention. The preparation of the carboxylic esters II had already 15 been described for some instances, or it takes place by usual chemical methods. Compounds in which X is a bond are prepared by conventional aromatic coupling, for example Suzuki 20 coupling with boric acid derivatives and halides with palladium catalysis or copper-catalyzed coupling 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. ortho 25 phenyloxazolidines, or other organometallic compounds (cf. I.M. Dordor et al., J. Chem. Soc. Perkins Trans. I, 1984, 1247-52). Ether-bridged derivatives are prepared by alkylating 30 the corresponding alcohols or phenols with halides. The sulfoxides and sulfones can be obtained by oxidizing the corresponding thioethers. 35 Alkene- and alkyne-bridged compounds are prepared, for example, by the Heck reaction from aromatic halides and corresponding alkenes and alkynes (cf. I. Sakamoto et al., Chem. Pharm. Bull., 1986, 34, 2754-59).

0050/48969 - 16 The chalcones are produced by condensing acetophenones with aldehydes and can, where appropriate, be converted into the analogous alkyl derivatives by hydrogenation. 5 Amides and sulfonamides are prepared from the amines and acid derivatives in analogy to the methods described above. The dialkylaminoalkyl substituents are obtained by 10 reductive amination of the aldehyde derivatives with the appropriate amines in the presence of boron hydrides such as the BH 3 /pyridine complex or or [sic] NaBH 3 CN (A.F. Abdel-Magid, C.A. Maryanoff, K.G. Carson, Tetrahedron Lett. 10990 [sic], 31, 5595; A.E. Moormann, 15 Synth. Commun. 1993, 23, 789). The amides I with heterocyclic substituents of the present invention are inhibitors of cysteine proteases, especially cysteine proteases such as calpains I and II 20 and cathepsins B and L. The inhibitory effect of the amides I with heterocyclic substituents has been determined using enzyme assays known from the literature, determining as criterion of 25 effect a concentration of the inhibitor at which 50% of the enzyme activity is inhibited (= IC 50 ). The amides I were measured in this way for their inhibitory effect on calpain I, calpain II and cathepsin B. 30 Cathepsin B assay The inhibition of cathepsin B was determined by a method analogous to that of S. Hasnain et al., J. Biol. Chem., 1993, 268, 235-40. 35 2 pl of an inhibitor solution prepared from inhibitor and DMSO (final concentrations: 100 pM to 0.01 gM) are added to 88 pl of cathepsin B (cathepsin B from human liver (Calbiochem), diluted to 5 units in 500 pM 0050/48969 - 17 buffer). This mixture is preincubated at room temperature (250C) for 60 minutes and then the reaction is started by adding 10 pl of 10 mM Z-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is followed in a 5 microtiter plate reader at 405 nM [sic] for 30 minutes. The IC 50 s are then determined from the maximum gradients. Calpain I and II assay 10 The testing of the inhibitory properties of calpain inhibitors takes place in buffer with 50 mM tris-HCl, pH 7.5; 0.1 M NaCl; 1 mM dithiotreithol [sic]; 0.11 mM CaCl 2 , using the fluorogenic calpain substrate 15 Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachem/ Switzerland). Human p-calpain is isolated from erythrocytes, and enzyme with a purity > 95%, assessed by SDS-PAGE, Western blot analysis and N-terminal sequencing, is obtained after several chromatographic 20 steps (DEAE-Sepharose, phenyl-Sepharose, Superdex 200 and blue Sepharose) . The fluorescence of the cleavage product 7-amino-4-methylcoumarin (AMC) is followed in a Spex Fluorolog fluorimeter at Xex = 380 nm and Xem = 460 nm. The cleavage of the substrate is linear in a 25 measurement range of 60 min., and the autocatalytic activity of calpain is low, if the tests are carried out at temperatures of 120C. The inhibitors and the calpain substrate are added to the test mixture as DMSO solutions, and the final concentration of DMSO ought 30 not to exceed 2%. In a test mixture, 10 pl of substrate (250 pM final) and then 10 pl of p-calpain (2 pg/ml final, i.e. 18 nM) are added to a 1 ml cuvette containing buffer. The 35 calpain-mediated cleavage of the substrate is measured for 15 - 20 min. Then 10 ptl of inhibitor (50-100 JM solution in DMSO) are added and the inhibition of cleavage is measured for a further 40 min.

0050/48969 - 18 Ki values are determined using the classical equation for reversible inhibition: (Methods in Enzymology, ) 5 Ki I(v0/vi)-l; where I = inhibitor concentration, vO = initial rate before addition of the inhibitor; vi = reaction rate at equilibrium. The rate is calculated from v = AMC liberation/time, 10 i.e. height/time. Calpain is an intracellular cysteine protease. Calpain inhibitors must pass through the cell membrane in order to prevent intracellular proteins from being broken 15 down by calpain. Some known calpain inhibitors, such as, for example, E 64 and leupeptin, cross cell membranes only poorly and accordingly show only a poor effect on cells, although they are good calpain inhibitors. The aim is to find compounds better able to 20 cross membranes. Human platelets are used to demonstrate the ability of calpain inhibitors to cross membranes. Calpain-mediated breakdown of tyrosine kinase pp60src 25 in platelets Tyrosine kinase pp60src is cleaved by calpain after activation of platelets. This has been investigated in detail by Oda et al. in J. Biol. Chem., 1993, Vol. 268, 30 12603-12608. This revealed that the cleavage of pp60src can be prevented by calpeptin, a calpain inhibitor. The cellular efficacy of our substances was tested based on this publication. Fresh, citrated, human blood was centrifuged at 200 g for 15 min. The platelet-rich 35 plasma was pooled 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 0, 0.24 mM NaH 2

PO

4 x H 2 0, 12 mM NaHCO 3 , 5.6 mM glucose, 1 mM EDTA, pH 7.4). After a centrifugation step and washing step with platelet 0050/48969 - 19 buffer, the platelets were adjusted to 107 cells/ml. The human platelets were isolated at RT. In the assay mixture, isolated platelets (2 x 106) were 5 preincubated with various concentrations of inhibitors (dissolved in DMSO) at 370C for 5 min. The platelets were then activated with 1 pM ionophore A23187 and 5 mM CaCl2. After incubation for 5 min., the platelets were briefly centrifuged at 13,000 rpm, and the pellet was 10 taken up SDS sample buffer (SDS sample buffer: 20 mM Tris-HCl, 5 mM EDTA, 5 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 5 pg/ml leupeptin, 10 pg/ml pepstatin, 10% glycerol and 1% SDS). The proteins were fractionated in a 12% gel, and pp60src and its 52 kDa and 47 kDa cleavage products 15 were identified by Western blotting. The polyclonal rabbit antibody used, anti-cys-src (pp6Oc-src), was purchased from Biomol Feinchemikalien (Hamburg). This primary antibody was detected using a second, HRP-coupled goat antibody (Boehringer Mannheim, FRG). 20 The Western blotting was carried out by known methods. The cleavage of pp60src was quantified by densitometry, using as controls unactivated (control 1: no cleavage) and ionophore- and calcium-treated platelets 25 (control 2: corresponds to 100% cleavage). The ED 5 o corresponds to the concentration of inhibitor at which the intensity of the color reaction is reduced by 50%. Glutamate-induced cell death in cortical neurones 30 The test was carried out as in Choi D.W., Maulucci Gedde M.A. and Kriegstein A.R., "Glutamate neuro toxicity in cortical cell culture". J. Neurosci. 1989, 7, 357-368. 35 The cortex halves were dissected out of 15-day old mouse embryos and the single cells were obtained enzymatically (trypsin). These cells (glia and cortical neurones) are seeded out in 24-well plates. After three 0050/48969 - 20 days (laminin-coated plates) or seven days (ornithine coated plates), the mitosis treatment is carried out with FDU (5-fluoro-2-deoxyuridines [sic]). 15 days after preparation of the cells, cell death is induced 5 by adding glutamate (15 minutes). After removal of glutamate, the calpain inhibitors are added. 24 hours later, the cell damage is estimated by determining lactate dehydrogenase (LDH) in the cell culture supernatant. 10 It is postulated that calpain is also involved 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). For this reason, in 15 another model, cell death was induced in a human cell line with calcium in the presence of a calcium ionophore. Calpain inhibitors must get inside the cell and inhibit calpain there in order to prevent the induced cell death. 20 Calcium-mediated cell death in NT2 cells Cell death can be induced in the human cell line NT2 by calcium in the presence of the ionophore A 23187. 25 105 cells/well were plated out in microtiter plates 20 hours before the test. After this period, the cells were incubated with various concentrations of inhibitors in the presence of 2.5 pLM ionophore and 5 mM calcium. 0.05 ml of XTT (Cell Proliferation Kit II, 30 Boehringer Mannheim) was added to the reaction mixture after 5 hours. The optical density was determined approximately 17 hours later, in accordance with the manufacturer's information, in an SLT Easy Reader EAR 400. The optical density at which half the cells 35 have died is calculated from the two controls with cells without inhibitors incubated in the absence and presence of ionophore.

0050/48969 - 21 Elevated glutamate activities occur in a number of neurological disorders of psychological disturbances and lead to states of overexcitation or toxic effects in the central nervous system (CNS). The effects of 5 glutamate are mediated by various receptors. Two of these receptors are classified, in accordance with the specific agonists, as NMDA receptor and AMPA receptor. Antagonists to these glutamate-mediated effects can thus be employed for treating these disorders, in 10 particular for therapeutic use for neurodegenerative disorders such as Huntington's chorea and Parkinson's disease, neurotoxic impairments after hypoxia, anoxia, ischemia and after lesions like those occurring after stroke and trauma, or else as antiepileptics (cf. 15 Arzneim. Forschung 1990, 40, 511-514; TIPS, 1990, 11, 334-338; Drugs of the Future 1989, 14, 1059-1071). De [sic] Protection from cerebral overexcitation by excitatory 20 amino acids (NMDA and AMPA antagonism in mice) Intracerebral administration of excitatory amino acids (EAA) induces such drastic overexcitation that it leads to convulsions and death of the animals (mice) within a 25 short time. These signs can be inhibited by systemic, e.g. intraperitoneal, administration of centrally acting substances (EAA antagonists) . Since excessive activation of EAA receptors in the central nervous system plays a significant part in the pathogenesis of 30 various neurological disorders, it is possible to infer from the detected EAA antagonism in vivo that the substances may have therapeutic uses for such CNS disorders. As a measure of the efficacy of the substances, an ED 5 o was determined, at which 50% of the 35 animals are free of signs, owing to the previous i.p. administration of the measured substance, by a fixed dose of either NMDA or AMPA.

0050/48969 - 22 The amides I with heterocyclic substituents are inhibitors of cysteine derivatives [sic] such as calpain I and II and cathepsin B and L, and can thus be used to control diseases associated with an elevated 5 activity of calpain enzymes or cathepsin enzymes. The present amides I can accordingly be used to treat neurodegenerative disorders occurring after ischemia, trauma, subarachnoid hemorrhages and stroke, and neurodegenerative disorders such as multi-infarct 10 dementia, Alzheimer's disease, Huntington's disease and epilepsies and, in addition, to treat 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 15 muscle cells, coronary vasospasms, cerebral vasospasms, cataracts of the eyes, restenosis of the blood vessels after angioplasty. In addition, the amides I may be useful in the chemotherapy of tumors and metastasis thereof and for treating disorders in which an elevated 20 interleukin-1 level occurs, such as inflammation and rheumatic disorders. The pharmaceutical preparations according to the invention comprise a therapeutically effective amount 25 of the compounds I in addition to conventional pharmaceutical ancillary substances. The active ingredients can be present in the usual concentrations for local external use, for example in 30 dusting powders, ointments or sprays. As a rule, the active ingredients are present in an amount of from 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight. 35 For internal use, the preparations are administered in single doses. From 0.1 to 100 mg are given per kg of body weight in a single dose. The preparation may be administered in one or more doses each day, depending on the nature and severity of the disorders.

0050/48969 - 23 The pharmaceutical preparations according to the invention comprise, apart from the active ingredient, the customary excipients and diluents appropriate for 5 the required mode of administration. For local external use it is possible to use pharmaceutical ancillary substances such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene 10 glyco (sic] stearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum and wool fat. Suitable examples for internal use are lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone. 15 It is also possible for antioxidants such as tocopherol and butylated hydroxyanisole, and butylated hydroxy toluene, flavor-improving additives, stabilizers, emulsifiers and lubricants to be present. 20 The substances which are present in the preparation in addition to the active ingredient, and the substances used in producing the pharmaceutical preparations, are toxicologically acceptable and compatible with the active ingredient in each case. The pharmaceutical 25 preparations are produced in a conventional way, for example by mixing the active ingredient with other [sic] customary excipients and diluents. The pharmaceutical preparations can be administered in 30 various ways, for example orally, parenterally, such as intravenously by infusion, subcutaneously, intra peritoneally and topically. Thus, possible presentations are tablets, emulsions, solutions for infusion and injection, pastes, ointments, gels, 35 creams, lotions, dusting powders and sprays.

0050/48969 - 24 Examples Example 1 5 2-((4-Phenylpiperazin-1-yl)methyl)benzoic acid N-(3 phenylpropan-1-al-2-yl) amide a) Methyl 2- (4-phenyl-l-piperazinylmethyl)benzoate 10 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 0 C for 5 h and then stirred at room temperature for 60 h. The excess potassium 15 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 resulted in 16.8 g (100%) of the 20 product. b) 2-(4-phenyl-l-piperazinylmethyl)benzoic acid 16.8 g of intermediate la were introduced into 25 150 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 30 equimolar amount of 1 M HCl. The reaction mixture was evaporated to dryness, and the residue was taken up in methanol/toluene. Removal of the solvent resulted in 15.2 g (86%) of the product, which still contained salt. 35 0050/48969 - 25 C) 2-( (4-Phenylpiperazin-1-yl)methyl)benzoic acid N (3-phenylpropan-1-ol-2-yl)amide 3.0 g of intermediate lb and 3 ml of triethylamine 5 were introduced into 50 ml of DMF. 5 g of sodium sulfate were added and the mixture was stirred for 30 min. 1.5 g of phenylalaninol, 1.4 g of HOBT and 2.1 g of EDC were successively added at OC, and the mixture was stirred at room temperature 10 overnight. The reaction mixture was poured into distilled water, made alkaline with NaHCO 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 15 magnesium sulfate. Removal of the solvent resulted in 2.5 g (59%) of the product. d) 2-((4-Phenylpiperazin-1-yl)methyl)benzoic acid N (3-phenylpropan-l-al-2-yl)amide 20 2.3 g of intermediate 1c were introduced into 50 ml of DMSO in the presence of 2.4 g of triethylamine, and 2.5 g of S0 3 /pyridine complex were added. The mixture was stirred at room 25 temperature overnight. The mixture was poured into 250 ml of distilled water, made alkaline with NaHCO 3 , saturated with NaCl and extracted with 100 ml of methylene chloride, and the organic phase was dried over magnesium sulfate. After 30 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, resulting in 1.9 g (71%) of the product. 35 H-NMR (d 6 -DMSO): 8 = 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.

0050/48969 - 26 Example 2 2- ( (4-Benzylpiperazin-1-yl)methyl) benzoic acid N- (3 phenylpropan-1-al-2-yl) amide 5 a) Methyl 2- ( (4-benzyl-1-piperazinyl)methyl)benzoate [sic] 10.0 g of methyl 2-chlorobenzoate and 9.6 g of 10 N-benzylpiperazine were reacted in 200 ml of DMF in the presence of 15 g of potassium carbonate at 100 0 C in analogy to Example la, resulting in 17.6 g (100%) of the product. 15 b) 2-((4-Benzyl-l-piperazinyl)methyl)benzoic [sic] acid 17.5 g of intermediate 2a in 150 ml of THF were hydrolyzed with 1.6 g of LiOH in 150 ml of water 20 in analogy to Example lb, resulting in 9.1 g (54%) of the product. c) 2-((4-Benzylpiperazin-1-yl)methyl)benzoic acid N (3-phenylpropan-l-ol-2-yl)amide 25 3.0 g of intermediate 2b were 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 in analogy to Example 1c, resulting in 2.0 g (46%) of 30 the product. d) 2-((4-Benzylpiperazin-1-yl)methyl)benzoic acid N (3-phenylpropan-l-al-2-yl)amide 35 1.5 g of intermediate 2c were oxidized in 40 ml of DMSO with 1.9 g of S0 3 /pyridine complex in 20 ml of DMSO in the presence of 2.3 ml of triethylamine in analogy to Example ld, resulting in 0.4 g (21%) of the product in the form of the fumarate.

0050/48969 - 27 'H-NMR (d 6 -DMSO): 6 = 2.1-2.3 (8H), 2.9-3.0 (lH), 3.3-3.6 (6H), 4.5 (lH), 6.6 (2H), 7.1-7.7 (14H), 9.7 (1H), 10.3 (lH) ppm. 5 Example 3 2-( (4-Benzylpiperazin-1-yl)methyl)benzoic acid N- (1 carbamoyl-1-oxo-3-phenylpropan-2-yl) amide 10 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 were reacted in 40 ml of 15 DMF with 0.7 ml of triethylamine, 1.0 g of 3-amino-2-hydroxy-4-phenylbutyramide hydro chloride, 0.6 g of HOBT and 0.9 g of EDC in analogy to Example 1c, resulting in 0.8 g (38%) of the product. 20 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 were oxidized in 20 ml of 25 DMSO with 0.7 g of S0 3 /pyridine complex in the presence of 0.8 g of triethylamine in analogy to Example ld, resulting in 0.1 g (18%) of the product in the form of the free base. 30 'H-NMR (d 6 -DMSO) : 6 = 2.3 (4H), 2.8-3.5 (8H), 5.3 (1H), 6.7-7.5 (16H), 7.8 (lH), 8.1 (1H), 10.3 (1H) ppm. Example 4 35 2- (4-( (3-Methylphenyl)piperazin-1-yl)methyl)benzoic acid N- (1-carbamoyl-1-oxo-3-phenylpropan-2-yl) amide 0050/48969 - 28 a) Methyl 2- (4- ( (3-methylphenyl) -1-piperazinyl) methyl)benzoate [sic] 4.0 g of methyl 2-chloromethylbenzoate and 4.4 g 5 of 3-methylphenylpiperazine were heated in 200 ml of DMF in the presence of 4.5 g of potassium carbonate at 140 0 C for 3 h. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases 10 were washed three times with saturated brine, dried over magnesium sulfate and concentrated, resulting in 6.5 g (92%) of the product. b) 2- (4- ( (3-Methylphenyl) -l-piperazinyl)methyl) 15 benzoic [sic] acid 5.9 g of intermediate 4a were dissolved in 75 ml of THF and hydrolyzed with 0.9 g of LiOH in 75 ml of water in analogy to Example 1b, resulting in 20 2.9 g (51%) of the product. c) 2- (4- ( (3-Methylphenyl)piperazin-1-yl)methyl) benzoic acid N-(l-carbamoyl-l-ol-3-phenylpropan-2 yl)amide 25 1.8 g of intermediate 4b were introduced into 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-phenylbutyramide hydrochloride 30 and 1.2 g of EDC were successively added, in analogy to Example 1c, resulting in 1.4 g (50%) of the product. d) 2-(4-((3-Methylphenyl)piperazin-1-yl)methyl) 35 benzoic acid N-(1-carbamoyl-l-oxo-3-phenylpropan 2-yl) amide 1.2 g of intermediate 4c were dissolved in 30 ml of DMSO and oxidized with 1.6 g of S0 3 /pyridine 0050/48969 - 29 complex in the presence of 1.5 ml of triethylamine in analogy to Example ld, resulting in 1.0 g (83%) of the product. 5 MS: m/e = 484 (M+) Examples 5 and 6 were synthesized in analogy to Example 1. 10 Example 5 3- ( (4-Phenylpiperazin-1-yl)methyl)benzoic acid N- (3 phenylpropan-1-al- 2 -yl) amide fumarate 15 1 H-NMR (d 6 -DMSO): 6 = 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), 7.8 (2H), 8.9 (1H), 9.7 (1H) ppm. 20 Example 6 3- ((4- (2-tert-Butyl-4-trifluoromethylpyrimidin-6-yl) homopiperazin-1-yl) methyl) benzoic acid N- (3-phenyl propan-1-al-2-yl) amide 25 MS: m/e = 568 (M++l) Example 7 30 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-methylamino methyl)benzoic acid 35 11.5 g of N-(3,4-dioxomethylene)benzyl-N methylamine and 15.5 g of triethylamine were introduced into [lacuna], and 15.0 g of 4-bromomethylbenzoic acid in 100 ml of THF were 0050/48969 - 30 added. The reaction mixture was briefly heated to reflux and then stirred at room temperature for 15 h. After filtering off the salts, the mother liquor was concentrated, and the residue was 5 dissolved in ethyl acetate and washed with water. The aqueous phase was made alkaline and extracted several times with ethyl acetate, resulting in 6.6 g (32%) of the product as a white solid. 10 b) 4-(N-(3,4-Dioxomethylene)benzyl-N-methylamino methyl)benzoic acid N-(3-phenylpropan-1-ol-2-yl) amide 4.4 g of intermediate 5a [sic] were introduced 15 into 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 successively added, in analogy to Example 1c, resulting in 2.3 g (40%) of the product. 20 c) 4-(N-(3,4-Dioxomethylene)benzyl-N-methylamino methyl)benzoic acid N-(3-phenylpropan-1-al-2-yl) amide 25 2.0 g of intermediate 5b [sic] were dissolved in 60 ml of DMSO and oxidized with 2.1 g of S0 3 /pyridine complex in the presence of 1.8 ml of triethylamine in analogy to Example ld, resulting in 1.3 g (68%) of the product. 30 'H-NMR (CF 3 COOD): 6 = 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. 35 MS: m/e = 430 (M*) Examples 8-28 were prepared in analogy to Example 7.

0050/48969 - 31 Example 8 4- (N-Benzyl-N-methylaminomethyl) benzoic acid N- (3 phenylpropan-1-al-2-yl) amide 5 1 H-NMR (CF 3 COOD): 8 = 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) ppm. 10 MS: m/e = 386 (M*) Example 9 4- (N- (4-Methoxy) benzyl-N-methylaminomethyl) benzoic acid 15 N- (3-phenylpropan-l-al-2-yl)amide 1 H-NMR (CF 3 COOD): 6 = 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. 20 MS: m/e = 416 (M*) Example 10 25 4- (N-Benzyl-N-methylaminomethyl) benzoic acid N- (3 butan-1-al-2-yl)amide 1 H-NMR (CF 3 COOD): 8 = 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), 30 7.3-7.6 (5H), 7.8 (2H), 8.3 (2H) ppm. MS: m/e = 338 (M*) Example 11 35 4- (N- (3, 4-Dioxomethylene) benzyl-N-methylaminomethyl) benzoic acid N-(3-butan-1-al-2-yl)amide 0050/48969 - 32 1 H-NMR (CF 3 COOD): 0 = 1.1 (3H), 1.6 (2H), 1.9 (2H), 2.9 (3H), 4.25-4.6 (4H), 4.75 (1H), 6.1 (2H), 6.6 (1H), 6.9 (3H), 7.8 (2H), 8.3 (2H) ppm. 5 MS: m/e = 382 (M+) Example 12 4- (N- (4-Methoxy) benzyl-N-methylaminomethyl) benzoic acid 10 N-(3-butan-1-al-2-yl)amide MS: m/e = 368 (M*) Example 13 15 4- (N- (3, 4-Dioxomethylene ) benzyl-N-methylaminomethyl) benzoic acid N- (3-cyclohexylpropan-1-al-2-yl) amide 'H-NMR (CF 3 COOD): 8 = 1.0-2.0 (13H), 2.9 (3H), 4.3-4.9 20 (4H), 6.1 (2H), 6.6 (1H), 6.9 (3H), 7.8 (2H), 8.3 (2H) ppm. MS: m/e = 436 (M+) 25 Example 14 4- (N- (4-Benzyl-N-methylaminomethyl) benzoic acid N- (3 cyclohexylpropan-1-al-2-yl) amide 30 1 H-NMR (d 6 -DMSO): 8 = 1.0-1.8 (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 (iH) ppm. Example 15 35 4- (N- (4-Methoxy) benzyl-N-methylaminomethyl) benzoic acid N-(3-cyclohexylpropan-1-al-2-yl)amide 0050/48969 - 33 1 H-NMR (CDC1 3 ): = 1-0-1.8 (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. 5 Example 16 4- ( (2-Phenylpyrrolid-1-yl)methyl)benzoic acid N- (3 cyclohexylpropan-1-al-2-yl) amide 10 MS: m/e = 420 (M*) Example 17 4- ( (2-Phenylpyrrolid-1-yl)methyl) benzoic acid N- (3 15 butan-1-al-2-yl)amide MS: m/e = 364 (M+) Example 18 20 4- ( (2-Phenylpyrrolid-1-yl)methyl)benzoic acid N- (3 phenylpropan-1-al-2-yl)amide MS: m/e = 412 (M+) 25 Example 19 4- ((1,2, 3,4-Dihydroquinolin-1-yl)methyl)benzoic acid N (3-cyclohexylpropan-1-al-2-yl)amide 30 'H-NMR (CDC1 3 ): 6 = 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. 35 MS: m/e = 404 (M+) 0050/48969 - 34 Example 20 4- ((1,2, 3,4-Dihydroquinolin-1-yl)methyl)benzoic acid N (3-phenylpropan-1-al-2-yl) amide 5 1 H-NMR (d 6 -DMSO): 8 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 (1H), 9.5 (1H) ppm. 10 MS: m/e = 398 (M') Example 21 15 4- ((1,2, 3,4-Dihydroquinolin-1-yl)methyl)benzoic acid N (3-butan-1-al-2-yl)amide 'H-NMR (d 6 -DMSO): 8 = 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 20 (2H), 7.8 (2H), 8.8 (1H), 9.5 (1H) ppm. MS: m/e = 350 (M*) Example 22 25 4- ((1,2, 3,4-Dihydroisoquinolin-2-yl)methyl)benzoic acid N-(3-cyclohexylpropan-1-al-2-yl)amide 'H-NMR (d 6 -DMSO): 8 = 0.9-1.8 (13H), 2.7-2.9 (4H), 3.6 30 (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') 35 Example 23 4- ((1,2,3, 4-Dihydroisoquinolin-2-yl)methyl)benzoic acid N-(3-phenylpropan-1-al-2-yl)amide 0050/48969 - 35 IH-NMR (d 6 -DMSO): 6 = 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. 5 MS: m/e = 398 (M*) Example 24 10 4- ((1,2,3, 4-Dihydroisoquinolin-2-yl)methyl)benzoic acid N- (3-butan-1-al-2-yl) amide hydrochloride 'H-NMR (d 6 -DMSO): 8 = 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), 15 8.0 (2H), 9.0 (1H), 9.5 (1H), 11.75 (1H) ppm. Example 25 4- ((6, 7-Dimethoxy-1, 2,3, 4-dihydroisoquinolin-2-yl) 20 methyl) benzoic acid N- (3-cyclohexylpropan-l-al-2-yl) amide 1 H-NMR (d 6 -DMSO): 6 = 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 25 (1H), 7.5 (2H), 7.8 (2H), 8.8 (1H), 9.5 (1H) ppm. MS: m/e = 464 (M*) Example 26 30 4- ( (6,7-Dimethoxy-1,2,3,4-dihydroisoquinolin-2-yl) methyl)benzoic acid N- (3-phenylpropan-l-al-2-yl)amide 1 H-NMR (d 6 -DMSO): 8 = 2.7 (4H), 2.9 (1H), 3.25 (1H), 3.6 35 (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) ppm. MS: m/e = 458 (M+) 0050/48969 - 36 Example 27 4- ( (6,7-Dimethoxy-1,2,3,4-dihydroisoquinolin-2-yl) methyl)benzoic acid N-(3-butan-l-al-2-yl)amide 5 1 H-NMR (d 6 -DMSO): 5 = 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 (1H), 6.6 (1H), 6.7 (1H), 7.4 (2H), 7.8 (2H), 8.8 (1H), 9.5 (1H) ppm. 10 MS: m/e = 410 (M') Example 28 15 2-( (1,2,3,4-Dihydroquinolin-1-yl)methyl)benzoic acid N (3-butan-l-al-2-yl)amide MS: m/e = 441 (M+) 0050/48969 -37 LA 0 0 0 0 N 0 04 0050/48969 - 38 U' P40 Or_ _ 5 z z a 0 00 P-m u 4 UU u u 0 0 >1 -4 zq z z 0050/48969 - 39 U, N N r z z 0 0 0 u u z I 4w 4 4 w / 4w 00 0 0 0 z N N N 0 0 0 0 I -4 4- 4 0050/48969 -40 In 00 z z N4W 4W Aw4W N4W 00 0 0 0 Iz- im u u u z LA 0050/48969 -41 0 00 0 0 4vN 4 Nv 0 0 0 0 0 4-) pqz M _ m___ z 0 1 qm1 C1 C C13 q eq elq 0050/48969 -42 0 0 u uU N00 0 0 0 (*4 z 0n 0 00

N-N

0050/48969 -43 LA z z 0 0 L) U_ _ uu x rq N 04 4v 04V a~/ A >1 U z i B/ z or4N 4 . m nM 0050/48969 - 44 02 zz 0 0 0 Q U U z z z 0= N 4w A4 4 Mo 0 0 0 4 C Z6 0050/48969 -45 Ln z 0 z z onNvAw 4 A4VV C4 4 4U. ('4 4j 4-) z z Z 0 0 0 I-ICI Nr 10 0050/48969 - 46 0 4w 4- 4- 4w a ~ 0 0 0 0 r44 0I 0 1 '-S as Lnz 0050/48969 - 47 zz N eq 0 0 wA 0==V ,4w+ 4vv + z z2 o0 0 0 0 * U2 >1 z0 T- q n1 Ln LA ULA Ln LA 0050/48969 -48 Ln Nz o~ 0 0 c0 U) L) U U z n7 UnL)L nL 0050/48969 -49 LA z 000 N>N 0~ 0 iv4W iv 0 0 U w % 0050/48969 -50 0 0 0. UU z z r-3LN e.A4 U~ C40 ra z z z -41 04 0050/48969 -51 00 N lot 4v N z 00 0 0 0 C-)U u N N C4 N 0 0 0 0 0 z z 0 __j0 _ _ _ _ _ _ ci 2 z~ r- E- - 0050/48969 -52 z ~z 0 0 0 z 0== r~~4 i4w 0 0 0 0 0 u uN N N N N N z z z \dj 2M C.- 0\/C 0050/48969 -53 L, z C C 0 _ _ _ _ _ _ _ U U x A4 W ~ 4W A4W 0 0 u 4: N 'q r4I C 0 0 0 0 44.J 0 0 r z 4 co co00 c 0050/48969 -54 z 0 ~0 u ~U 4 04 Uz 0 N z o 0D co 0c 0050/48969 -55 In 0 0

OC

z z C4NNN Nl a 0 zz C19 N 0 0 0 0 0050/48969 - 56 z z z 0 0 0 ____ U 00 I 0 0 d4V 0 0 riM0 0N zz iI C1 000 (-4 (' __ _ 0f0 m ID c 0050/48969 -57 Ln 0 0 0 4w0 z1 0 0 04 0 110 0 0 z 0D 0000 1-4 r-4 1-I -4V 0050/48969 -58 LnN zz 0 (N 0 L ) K _ _ _ _ ___ _ __0 0 0 04 C14 Ln Go -4- 0050/48969 -59 UO, 0 0 0 A4 NU +) m _ _ _ _ 0 0 _ _ 110 0 0 0 4 .4:l om o- C-4 :1 r4 0050/48969 -60 Ln z z c )c I A4V 0 0 0 0 0 0 0 0 0 0 0i 0 0 0 z - -4 I-I V- w 4 v-4 0050/48969 -61 U, z L) C143 A4VV 04 0 10 zcl C4 C9 cl C~l 1- -4 r-4 T-4 1 -1 0050/48969 -62 U, z 0 C) 0 z z Z 0~ 0 G 3 c 4W A4W 4W r4n -e ____ 0 0 0__ dN z C1 C9 IO4 I - 4 I, T1 0050/48969 - 63 I\ / \ \ / c O M 0 0 0 U U U u U '1 04 U U 040 /\\ / \ / H 0l I - 0050/48969 -64 U, 0 0 z z 4.N 4V 00 0: 0 0 0 >1 0 0 E-f E-4 C1 com C,, 0050/48969 -65 z 2z 00 0 0 N ivw0 0 rli C4 0 00 0 0 0 T'4-e 0050/48969 - 66 Ln 41 4 r41 0 0 .4 C4- m 0 0 0 0 1I 01 0 L) u a4 0 2 I-I 1- 0050/48969 -67 04 0 N N 0 00 00U U 4. 0 0 0 0 0v 2nLnL Ln 0050/48969 -68 zz z 0 0 0 u\ ' zz 0~4 0 A~ A (N 0 0 (N (N0 U Euu 0 z00 In LA Ul LA Ul L -4H-- H- -4rI - 0050/48969 -69 U, r9 w 0 0 Ix 0) V it0 0 0 00 0 %0 0 0o o- '9 'l - I 0050/48969 -70 tn 0 0 N N AU I I z 0 0 U 0 0 0 0 N N N C4 x x x x' U U 3 -4 0 E- 0 Z _____ 6nOoO toI v.4% 0050/48969 -71 In 040 C4 N 41' 0 49E0 a, (D0

H

0050/48969 - 72 LA 0 0 00 NO N 0 0 0 0 0 o o mc 0050/48969 - 73 N A zzz o0 00 N /Z A4W + 0v C) 0 0 0 0 0 00 0a 00 c0 r' r4 coI I

I

0050/48969 -74 Ln (9:14 C4 0 0 I IN N C4 C) ) aj P4 E 0 00c oO 0050/48969 - 75 z z 0 0 a. U4 Z/ _- _4 0 o 0 0 -I (N N en 0 0 m0a 0050/48969 - 76 Ltl z z 0 0 0 C) LN x~ z/ U~ C 0 [24 0_ _ ____ +_ _ ) _ _ 134 m 0 0 (.4 0 11 00 04 N 0 I -44 4>1 >1 0 04P4 N E 6c z 04 '4'- 0050/48969 -77 Ln 00 U(-4 K 3 z 4,4 4 .4 4, 4 0 0 0 0 0 04. 0 C4eq( 0 0 0 0 0 C4 Mq Nqeq 0050/48969 -78 In C4C 11 0 Nn W r- o O 0 D 400 C4 eq e 0050/48969 -79 0 0 0o 44 uu U :4 / u L 44 >1 U ~ 0 zN -N I 0050/48969 -80 z o U~ L)_ __ _ _ C) /M I C-4 00 0 0 E-4 1 4 NolCl x Cl oM Lo0 0 z C4 C9 C4 CN i 0050/48969 - 81 LO eq z z 00 0 wu _ _K Nv4 r4 0q 0 0 0 00 zz 0050/48969 -82 Lfl C-4 wN K C4 K/4A, ,4w4ww ft n 0 0 u ) L)u 0 0 0 0 01 (N N ((N 0 >1 0 0050/48969 -83 In z 0 0 UU /~f~zz I \ I \ N ~4v 1w 4W41 4 0 0 m 0c0 0 0 C) U u U u 00 SC.IA Nq 0050/48969 -84 LA CN z f, C4 00. 0. Ix C14 (1 1 9 % 0050/48969 -85 0 0 0 P4_ _ _ _ A 4w 4W A4W v=AK(% 1 A0 00 0 0 0 0 '-4 >1 >10 m E-1 0 .- A dN 0050/48969 -86 e4q o 0 u z U U E-0 0 0 C..' C4qC1 1 0050/48969 -87 inq z 00 0 / eq z0 0 0 0 0 U U ueq u 0 04 N m6' Un Ln Un Un C14 c C4 ci C0 0050/48969 - 88 In c z z o0 0 0 U V 14v 0 0 U L -4: 01 0 0 0

'-I

zLn Ln LA) Ln Ln z q elq CA eq L eq 0050/48969 -89 C~C4 00 u r4 0 0 ~ U U U 6' ' (Al (x) A, 0050/48969 -90 zz z o0 0Z a4 A4U 4s 4v 4 0 0 0 00 a a. 04C C14 C14 C4C9C 0050/48969 -91 04. ____ _ __ ___ K _ _C_ IxO 2 z Kuz ,4w 4N 0 0 0 0 0 0 Z 0 0 >1 04 0 a4 aA r- r- -.

0050/48969 - 92 zz W 0 C40 C)0 0 N) xZ 00 0 0 0 0 0 0 ~ z z ____ z

C

C14 ~ l C4 C* C1 0050/48969 -93 Lfn z OZ 0 U U 4 TN 0 00 U 0 000 0o Go. I

I

0050/48969 -94 U, z z 0 0 0 w 4w 4w 4w 4w 0 0 0 0 01 0 0 -4 0050/48969 -95 LA z 0 0 0 41 W 4w= Aw 4w m- 0 0 0 0 U~ L.) U N i 0 0 N 4N Nl >10 0 a I E-4 0 a-I (4 z 0 %0 %0 0050/48969 -96 U' z zz A A 1j 1 0 0 0 0 'E-4 oN 07%C II IIq 01 C 0050/48969 -97 Lnq z UU UU 0 0 eqa eq

Claims

1. An amide of the formula I (RC2) R 4 R1 5 and its tautomeric and isomeric forms, possible enantiomeric and diastereomeric forms, and pos sible physiologically tolerated salts, in which 10 the variables have the following meanings: Ri can be hydrogen, C 1 -C 6 -alkyl, branched and unbranched, phenyl, naphthyl, quinolyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, 15 quinazolyl, quinoxalyl, thienyl, benzo thienyl, benzofuranyl, furanyl and indolyl, it being possible for the rings also to be substituted by to 3 R 6 radicals, and 20 R2 are hydrogen, Ci-C-alkyl, branched or unbranched, O-Ci-C-alkyl, branched or unbranched, C

2 -C-alkenyl, C 2 -C-alkynyl, C 1 -C-alkyl-phenyl, C 2 -C-alkenyl-phenyl, C 2 -C-alkynyl-phenyl, OH, Cl, F, Br, I, CF 3 , 25 NO 2 , NH 2 , CN, COOH, COO-Ci-C 4 -alkyl, NHCO-C-C 4 -alkyl, NHCO-phenyl, CONHR 9 , NHSO 2 -C-C 4 -alkyl, NHSO 2 -phenyl, S0 2 -C 1 -C 4 alkyl and S0 2 -phenyl, and 30 R3 can be NR7 R or a ring such as 0050/48969 - 99 -N N-R$ - *N D R -- N O-- N -- -Re -0N (R' (R) (R R 4 is -Ci-C 6 -alkyl, branched or unbranched, which may also carry a phenyl, pyridyl, thienyl, 5 cyclohexyl, indolyl or naphthyl ring which is in turn substituted by a maximum of two R 6 radicals, and R 5 is hydrogen, COOR1 and CO-Z in which Z is 10 NR1 2 R 13 and R7 -N N-N' -N -7 N and R6 is hydrogen, Ci-C 4 -alkyl, branched or unbranched, -O-Ci-C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO-Ci-C 4 -alkyl, 15 -NHCO-Ci-C 4 -alkyl, -NHCO-phenyl, -NHSO 2 -C 1 -C 4 alkyl, -NHSO 2 -phenyl, -S0 2 -Ci-C 4 -alkyl and -S0 2 -phenyl, and R 7 is hydrogen, Ci-C-alkyl, linear or branched, 20 and which may be substituted by a phenyl ring which itself may also be substituted by one or two R1 0 radicals, and R is hydrogen, Ci-C 6 -alkyl, linear or branched, 25 which may be substituted by a phenyl ring which may itself also be substituted by one or two R1 0 radicals, and R 9 is hydrogen, Ci-C 6 -alkyl, branched or 30 unbranched, which may also carry a sub- 0050/48969 - 100 16 stituent R1 , or phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrazyl, naphthyl, quinolyl, imidazolyl, which may also carry one or two substituents R 4 , and 5 S10 can be hydrogen, Ci-C 4 -alkyl, branched or unbranched, -O-Ci-C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO-Ci-C 4 -alkyl, -NHCO-Ci-C 4 -alkyl, -NHCO-phenyl, -NHSO 2 -Ci-C 4 10 alkyl, -NHSO 2 -phenyl, -S0 2 -Ci-C 4 -alkyl and -S0 2 -phenyl R 1 is hydrogen, Ci-C 6 -alkyl, linear or branched, and which may be substituted by a phenyl ring 15 which may itself also be substituted by one or two R' 0 radicals, and Ri2 is hydrogen, Ci-C 6 -alkyl, branched and unbranched, and 20 -N N--' -N R' -N -N-N 7 -N-O . N--n -(CH 2 )N [sic] R13 is hydrogen, Ci-C 6 -alkyl, branched or unbranched, which may also be substituted by 25 a phenyl ring which may also carry an Rio radical, and by [lacuna] and R14 is hydrogen, Ci-C 6 -alkyl, branched or 30 unbranched, O-C 1 -C 6 -alkyl, branched or unbranched, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO-Ci-C 4 -alkyl, or two R1 4 radicals may represent a bridge OC(Ris)20, and 0050/48969 - 101 R i is hydrogen, Ci-C 6 -alkyl, branched and unbranched, and R i can be a phenyl, pyridyl, pyrimidyl, 5 pyridazyl, pyrazinyl, pyrazyl, pyrrolyl, naphthyl, quinolyl, imidazolyl ring, which may also carry one or two substituents R 6 , and 10 A is -(CH 2 )m-, -(CH 2 )m -0-(CH 2 )o-, -(CH 2 )o-S-(CH 2 )m-, -(CH 2 )o-SO-(CH 2 )m-, - (CH 2 ) o-SO2- (CH 2 )m-, -CH=CH-, -C=C-, -CO-CH=CH-, - (CH 2 ) o-CO- (CH2) m-, - (CH 2 ) m-NHCO- (CH 2 ) o-, - (CH 2 ) m-CONH- (CH 2 ) o-, 15 - (CH 2 ) m-NHSO 2 - (CH 2 ) o-, -NH-CO-CH=CH-, - (CH 2 ) m-SO 2 NH- (CH 2 ) o-, -CH=CH-CONH- and b b6N N and 0 0 H [sic] R 1 -A together are also 20 [lacuna] and B is phenyl, pyridine, pyrimidine, pyrazine, imidazole and thiazole, and 25 x is 1, 2 or 3, and n is a number 0, 1 or 2, and 30 m, o is, independently of one another, a number 0, 1, 2, 3 or 4. 0050/48969 - 102 2. An amide with heterocyclic substituents, of the formula I, as claimed in claim 1, where 5 B is pyridine or phenyl, and R 5 is hydrogen, and R 9 hydrogen, Ci-C-alkyl, branched or unbranched, 10 which [lacuna] also carry a substituent R 1 , R1 6 phenyl which may also carry one or two sub stituents R 14 , and 15 n 0 and 1, and x 1.

3. An amide with heterocyclic substituents, of the 20 formula I, as claimed in claim 1, where B is pyridine or phenyl, and R is CONR2 R , and 25 R 9 hydrogen, Ci-C 6 -alkyl, branched or unbranched, 166 which [lacuna] also carry a substituent R, R phenyl which may also carry one or two sub 30 stituents R1 4 , and n 0 and 1, and x 1. 35

4. An amide with heterocyclic substituents, of the formula I, as claimed in claim 1, where B is pyridine or phenyl, and 0050/48969 - 103 R 2 is hydrogen R 5 is hydrogen, and 5 R 9 hydrogen, Ci-C 6 -alkyl, branched or unbranched, which [lacuna] also carry a substituent R 1 , R 1 phenyl which may also carry one or two sub 10 stituents R 14, and n 0 and 1, and x 1. 15

5. An amide with heterocyclic substituents, of the formula I, as claimed in claim 1, where B is pyridine or phenyl, and 20 R2 is hydrogen R is CONR 12R , and 25 R 9 hydrogen, C 1 -C-alkyl, branched or unbranched, which [lacuna] also carry a substituent R 16 , R 16 phenyl which may also carry one or two sub stituents R 14, and 30 n 0 and 1, and x 1. 35

6. An amide with heterocyclic substituents, of the formula I, as claimed in claim 1, where A is -(CH 2 )m-, -(CH 2 )m-0-(CH 2 )o-, - (CH 2 ) oS (CH 2 )m-, -CH=CH-, -C=C-, 0050/48969 - 104 - (CH 2 ) -CONH- (CH 2 )o-, - (CH 2 ) m-SO 2 NH- (CH 2 ) o-, and B is pyridine or phenyl, and 5 R 2 is hydrogen, and RE 5is hydrogen, and 10 R 9 hydrogen, CI-C 6 -alkyl, branched or unbranched, which may also carry a sub stituent R 1 6, and R 16 phenyl, and 15 m, n, o 0 and 1, and x 1. 20

7. An amide with heterocyclic substituents, of the formula I, as claimed in claim 1, where A is -(CH 2 )m-, -(CH 2 )m-0-(CH 2 )o-, - (CH 2 ) oS (CH 2 )m-, -CH=CH-, -C=C-, 25 - (CH 2 )m-CONH- (CH 2 ) o-, - (CH 2 )m-SO 2 NH- (CH 2 ) o-, and B is pyridine or phenyl, and 30 R2 is hydrogen Ra 5is CONRi 2 R 13 , and R 9 hydrogen, Ci-C 6 -alkyl, branched or 35 unbranched, which may also carry a sub stituent R 1 , and R 16 phenyl, and 0050/48969 - 105 m, n, o 0 and 1, and x 1. 5

8. An amide with heterocyclic substituents, of the formula I, as claimed in claim 1, where B is pyridine or phenyl, and 10 R 1 , R 2 are hydrogen, and RE 5is hydrogen, and 15 R hydrogen, Ci-C 6 -alkyl, branched or unbranched, which may also carry a sub stituent Ri6, and RM phenyl, and 20 m, n, o 0, and x 1. 25

9. An amide with heterocyclic substituents, of the formula I, as claimed in claim 1, where B is pyridine or phenyl, and 30 R , R2 are hydrogen R 5is CONR R 1 3 , and R hydrogen, Ci-C-alkyl, branched or 35 unbranched, which may also carry a sub stituent R 1 6 , and R 16 phenyl, and 0050/48969 - 106 m, n, o 0 x 1. 5

10. The use of amides of the formula I as claimed in claims 1-5 for treating diseases.

11. The use of amides of the formula I as claimed in claims 1-5 as inhibitors of cysteine proteases. 10

12. The use as claimed in claim 6 as inhibitors of cysteine proteases such as calpains and cathepsins, in particular calpains I and II and cathepsins B and L. 15

13. The use of amides of the formula I as claimed in claims 1-5 for production as pharmaceuticals for treating diseases in which elevated calpain activities occur. 20

14. The use of amides of the formula I as claimed in claims 1-5 for producing pharmaceuticals for treating neurodegenerative disorders and neuronal damage. 25

15. The use as claimed in claim 9 for treating neurodegenerative disorders and neuronal damage induced by ischemia, trauma or massive bleeding. 30

16. The use as claimed in claim 10 for treating stroke and craniocerebral trauma.

17. The use as claimed in claim 10 for treating Alzheimer's disease and Huntington's disease. 35

18. The use as claimed in claim 10 for treating epilepsies. 0050/48969 - 107

19. The use of compounds of the formula I as claimed in claims 1-5 for producing pharmaceuticals and [sic] treating damage to the heart after cardiac ischemias, damage to the kidneys after renal 5 ischemias, skeletal muscle damage, muscular dystrophies, damage produced by proliferation of smooth muscle cells, coronary vasospasm, cerebral vasospasm, cataracts of the eyes and restenosis of blood vessels after angioplasty. 10

20. The use of amides of the formula I as claimed in claims 1-5 for producing pharmaceuticals for treating tumors and metastasis thereof. 15

21. The use of amides of the formula I as claimed in claims 1-5 for producing pharmaceuticals for treating disorders in which elevated interleukin-1 levels occur. 20

22. The use of amides according to claims 1-5 for treating immunological disorders such as inflamma tions and rheumatic disorders.

23. A pharmaceutical preparation for oral, parenteral 25 or intraperitoneal use, comprising at least one amide I as claimed in claims 1-5 per single dose, besides conventional pharmaceutical ancillary substances.