OA12907A - Use of IKB-kinase inhibitors for the treatment of pain. - Google Patents

Abstract

The invention relates to the use of IkappaB kinase inhibitors that are suitable for producing medicaments for the treatment of pain. Suitable inhibitors are produced from compounds of formulas (I) and (Ia).

Description

1 012907

Description

Use of ΙκΒ-kinase inhibitors in pain therapy

The invention relates to the use of ΙκΒ-kinase inhibitors for treating pain.

Patent applications WO 01/00610, WO 01/30774 and WO 01/68648describe compounds which are able to modulate NFkB. NFkB is a heterodimeric transcription factor which is able to activate a largenumber of genes which encode, inter alia, proinflammatory cytokines suchas IL-1, IL-2, TNFa or IL-6. NFkB is présent in the cytosol of cells, where itis complexed with its naturally occurring inhibitor IkB. Stimulation of thecells, for example by cytokines, leads to the IkB being phosphorylated andsubsequently broken down proteolytically. This proteolytic breakdown leadsto the activation of NFkB, which then migrâtes into the nucléus of the cell,where it activâtes a large number of proinflammatory genes.

In diseases such as rheumatoid arthritis (in connection with inflammation),osteoarthritis, asthma, cardiac infarction, Alzheimer’s diseases oratherosclerosis, NFkB is activated to beyond the normal extent. Theinhibition of NFkB is also of value in the treatment of cancer since it is usedin such treatment to augment the cytostatic therapy. It has beendemonstrated that pharmaceuticals such as glucocorticoids, salicylates orgold salts, which are used in the therapy of rheumatism, inhibit the NFkB-activating signal chain at various points or interfère directly with thetranscription of the genes.

The first step in said signal cascade is the breakdown of IkB. Thisphosphorylation is regulated by the spécifie IkB kinase.

Pharmaceuticals belonging to a large number of different substance groupsare employed in treating acute and chronic pain. Despite this, the therapyof pain has still not been satisfactorily solved even today. This is due, inparticular, to the fact that the analgésies which are on the market do nothâve a sufficiently powerful effect.

In an endeavor to obtain active compounds for treating pain, it has nowbeen found that it is possible to use ΙκΒ-kinase inhibitors for this purpose. 012907 2

In particular, it has been possible to demonstrate, In the models employed,a strength of effect which is clearly superior to that of classical nonsteroidalanti-inflammatory agents.

The invention relates, therefore, to the use of ΙκΒ-kinase inhibitors forproducing pharmaceuticals for treating pain.

The term "pain” is understood as meaning acute pains and chronic pains.

The following are examples of chronic pains: chronic musculoskeletal diseases, such as back pains, pains associated with menstruel bleeding, pains associated with osteoarthritis or rheumatoid arthritis, pains associated with intestinal inflammation, pains associated with cardiac muscle inflammation, pains associated with multiple sclerosis, pains associated with neuritis, pains associated with carcinomas and sarcomas, pains associated with AIDS, pains associated with chemotherapy, amputation pain, trigeminus neuralgia, headaches, such as migraine cephalalgia, or neuropathie pains, such as post-herpes zoster neuralgia.

The following are examples of acute pains: pains following injuries, post-operative pains, pains in association with an acute attack of goût, or acute pains following jaw-bone surgery interventions.

Examples of ΙκΒ-kinase inhibitors are indole dérivatives or benzimidazoledérivatives as are described in the patent applications WO 01/00610 andWO 01/30774.

The invention furthermore relates to the use of compounds of the formula I 012907 3

R

and/or a stereoisomeric form of the compound of the formula I and/or aphysiologically tolerated sait of the compound of the formula I,for producing pharmaceuticals for treating pains, whereE is N atom or the radical -C(R19)-, where R19 is hydrogen atom or the radical R9,one of the substituents R1, R2, R3 and R4 is a radical of the formula II,

in which D is -C(O)-, -S(O)- or -S(O)2-, R8 is hydrogen atom or -(CrC^alkyl, R9 is 1. characteristic radical of an amino acid, 2. aryl, in which aryl is unsubstituted or substituted, 3. heteroaryl having from 5 to 14 ring members, in whichheteroaryl is unsubstituted or substituted, 4. heterocycle having from 5 to 12 ring members, inwhich heterocycle is unsubstituted or substituted, 5. -(Ci-Ce)-alkyl, in which alkyl is straight-chain orbranched and is unsubstituted or substituted, once,twice or three times, independently of each other, by 5.1 aryl, in which aryl is unsubstituted orsubstituted, 5.2 heteroaryl having from 5 to 14 ring members, inwhich heteroaryl is unsubstituted or substituted, 5.3 heterocycle having from 5 to 12 ring members, in which heterocycle is unsubstituted or substituted, 5.4 -O-R11, 5.5 =0, 5.6 halogen, 5.7 -CN, 5.8 -CFs, 5.9 -S(O)X-R11, in which x is the integer zéro, 1 or 2, 012907 5.10 -C(O)-O-R11, 5.11 -C(O)-N(R11)2, 5.12 -C(O)-R11, 5.13 -N(R11)2> 5.14 -(C3-C6)-cycloalkyl, 5.15 radical of the formula

R11 is Z is 5.16 radical of the formula - a) hydrogen atom, b) (Ci-C6)-alkyl, in which alkyl is unsubstituted orsubstituted once, twice or three times 1. aryl, in which aryl is unsubstituted orsubstituted, 2. heteroaryl having from 5 to 14 ring members, 3. heterocycle having from 5 to 12 ring members, 4. halogen, 5. -N-(C-i-C6)n-alkyl, in which n is the integer zéro,1 or 2 and alkyl is unsubstituted or substitutedonce, twice or three times, independently ofeach other, by halogen or by -C(O)-OH, 6. -O-(Ci-C6)-alkyl or 7. -C(O)-OH, c) aryl, in which aryl is unsubstituted or substituted, d) heteroaryl having from 5 to 14 ring members, or e) heterocycle having from 5 to 12 ring members, and,in the case of (R11)2, R11 has, independently of eachother, the meanings of a) to e), 1. aryl, in which aryl is unsubstituted or substituted, 2. heteroaryl having from 5 to 14 ring members, inwhich heteroaryl is unsubstituted or substituted, 3. heterocycle having from 5 to 12 ring members, inwhich heterocycle is unsubstituted or substituted, 4. -(Ci-C6)-alkyl, in which alkyl is substituted orunsubstituted 012907 5 5. -C(O)-R11, 6. -C(O)-O-R11 or 7 -C(O)-N(R11)2l or R8 and R9 form, together with the nitrogen atom and carbon atom to whichthey are in each case bonded, a heterocyclic ring of the formula lia,

in which D and Z are defined as in formula II, A is nitrogen atom or the radical -CH2-, B is oxygen atom, sulfur atom, nitrogen atom or the radical-ch2-, Xis oxygen atom, sulfur atom, nitrogen atom or the radical-ch2-, Yis absent or is oxygen atom, sulfur atom, nitrogen atom orthe radical -CH2-, or X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or 1,4- diazine radical, where the ring System which is formed by N, A, X, Y, B and carbon atomdoes not contain more than one oxygen atom, X is not oxygen atom, sulfuratom or nitrogen atom when A is nitrogen atom, does not contain morethan one sulfur atom, and contains 1, 2, 3 or 4 nitrogen atoms, and wherean oxygen atom and a sulfur atom are not présent simultaneously,where the ring System which is formed by N, A, X, Y, B and carbon atom isunsubstituted or is substituted, once, twice or three times, independently ofeach other, by (CrCeJ-alkyi, in which alkyl is unsubstituted or substituted,once or two times, by 1.1. -OH, 1.2. -(CrC6)-alkoxy, 1.3. halogen, 1.4. -no2, 1.5. -nh2, 1.6. -cf3, 1.7. methylenedioxyl, 1.8 -C(O), 1.9. -C(O)-CH3, 012907 6 1.10. -(C1-C4)-alkoxycarbonyl, 1.11. -CN, 1.12. -C(O)-OH, 1.13. -C(O)-NH2i 1.14. tetrazolyi, 1.15. phenyl,. 1.16. phenoxy, 1.17. benzyl or 1.18. benzyloxyor R9 and Z form, together with the carbon atoms to which they are in eachcase bonded, a heterocyclic ring of the formula Ile,

in which D, R8 and R11 are defined as in formula II, T is oxygen atom, sulfur atom, nitrogen atom or the radical -CHz-, W is oxygen atom, sulfur atom, nitrogen atom or the radical-CH2-, V is absent or is oxygen atom, sulfur atom, nitrogen atom orthe radical -CH2-, or T and V or V and W together form a phenyl, 1,2-diazine, 1,3-diazine or 1,4-diazine radical, where the ring System which is formed by N, T, V, W and two carbonatoms does not contain more than one oxygen atom, does notcontain more than one sulfur atom and contains 1, 2, 3 or 4 nitrogenatoms, where an oxygen atom and a sulfur atom are not présentsimultaneously, and where the ring System which is formed by N, T,V, W and two carbon atoms is unsubstituted or is substituted, once,twice or three timës, independently of each other, by thesubstituents which are defined above under 1.1. to 1.18., and the other substituents R1, R2, R3 and R4 in each case are, independently ofeach other, 1. hydrogen atom, 012907 2. halogen, 3. -(CrCeJ-alkyl, 4. heteroaryl having from 5 to 14 ring members, in which heteroarylis unsubstituted or substituted, 5. heterocycle having from 5 to 12 ring members, in whichheterocycle is unsubstituted or substituted, 6. -NO2, 7. -CN, 8. -0-(Co-C4)-aikylaryl, 9 -O-(CrC4)-alkyl, 10. -O-R11, 11. -N(R11)2, 12. -S(O)r-R11, in which r is the integer zéro, 1 or 2, or 13. -CF3i R5 is 1. hydrogen atom, 2. -OH or 3. =0, and R6 is 1. aryl, in which aryl is unsubstituted or substituted, 2. phenyl which is substituted once or twice by 2.1 -CN, 2.2 -NOz, 2.3 -O-(C1-C4)-alkyI, 2.4 -N(R11)2, 2.5 -NH-C(O)-R11, 2.6 -S(O)s-R11, in which s is the integer zéro, 1 or 2, 2.7 -C(O)-R11 or 2.8 -(CrC4)-alkyl-NH2, 3. heteroaryl having from 5 to 14 ring members, is unsubstituted oris substituted once, twice or three times, or 4. heterocycle having from 5 to 12 ring members, is unsubstitutedor is substituted once, twice or three times.

The invention furthermore relates to the use, according to the invention, ofthe compound of the formula I, whereE is N atom or the radical -C(R19)-, where R19 is hydrogen atom or the radical R9,one of the substituents R1, R2, R3 and R4 is a radical of the formula II, inwhich

Dis -C(O)-,-S(O)-or-S(O)2-,

R8 is hydrogen atom or -(CrC4)-alkyl, R9 is 1. a characteristic radical of an amino acid which is derived from anaturally occurring α-amino acid of the group alanine, valine,leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine,threonine, cysteine, méthionine, asparagine, glutamine, lysine,histidine, arginine, glutamic acid and aspartic acid, 2. a characteristic radical of an amino acid which is derived from anamino acid which is not naturally occurring, such as 2-amino-adipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid,1,2,3,4,-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 3-(2-thienyl)alanine, 3-(3-thienyl)aIanine, sarcosine, pipecolic acid,2-aminoheptanoic acid, hydroxylysine, N-methylisoleucine, 6-N-methyllysine, norleucine, N-methylvaline, norvaline, omithine,allo-isoleucine, 4-hydroxyproline, allo-hydroxylysine, allo-threonine, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homocystéine, homophenylalanine, homo-cysteic acid, 2-amino-3-phenylaminoethyIpropionic acid, 2- amino-3-phenylaminopropionic acid, homotryptophan, cysteicacid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)-alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluoro-phenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine,4-nitrophenylalanine, cyclohexylalanine, 4-aminophenylalanine,citrulline, 5-fluorotryptophan, 5-methoxytryptophan, méthioninesulfone, méthionine sulfoxide or -NH-NR11-CON(R11)2, in whichR11 is defined as below, 3. aryl, from the group anthryl, biphenylyl, 2-biphenylyl, 3- biphenylyl, 4-biphenylyl, fluorenyl, naphthyl, 1-naphthyl,2-naphthyl or phenyl, in which aryl is unsubstituted or substitutedonce, twice or three times by identical or different radicals fromthe sériés -C(O)-(CrC4)-alkyl, -C(O), =0, -NH-(CrC4)-alkyl,-NH-((Ci-C4)-alkyl)2, -(Ci-C8)-alkyl, -(C-i-C8)-alkoxy, halogen,nitro, amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(CrC4)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl,methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,hydroxycarbonyl, aminocarbonyl, -(CrC4)-alkoxycarbonyl,phenyl, phenoxy, benzyl, benzyloxy, -S(O)X-R11 in which x is the 012907 integer zéro, 1 or 2, -O-(Ci-C4)-alkyl, -C(O)-OH, -C(O)-O-(CrC4)- alkyl, -NH-C(O)-(CrC4)-alkyl or tetrazolyl, 4. heteroaryl having from 5 to 14 ring members, in which heteroarylis unsubstituted or substituted and, as a radical, is derived fromthe group azepine, azetidine, benzimidazole, benzodioxolane,2-benzofuran, benzothiazole, benzothiophene, 2-benzo-thiophene, 2-benzoxazole, β-carboline, quînoxaline, quinazoline,quinoline, 2-quinoxaline, cyclohepta[b]-5-pyrrole, diazepine,dihydropyridine, 3-hydroxypyrro-2,4-dione, imidazole, 4- imidazole, imidazolidine, imidazoline, indazole, indole,isoquinoline, isoindole, isothiazole, isothiazolidine, isoxazole, 2- isoxazolidine, isoxazolidine, isoxazolone, methylimidazole, 3- (N-methylpyrrolidine), morpholine, oxazole, 1,3,4-oxadiazole,oxadiazolidinedione, oxadiazolone, 5-oxo-4,5-dihydro- [1,3,4]oxadiazole, 5-oxo-1,2,4-thiadîazole, 1,2,3,5-oxathia-diazole-2-oxide, 1-oxo-1,2-dihydro-3-isoquinol, phenylpyrrole, 5- phenyl-2-pyrrole, phthalazine, piperazine, piperidine, pyrazine,pyrazole, pyrazoiine, pyrazolidine, pyrazoline, pyridazine,pyrimidine, pyridine, pyridyl-N-oxide, 2-pyrrole, 3-pyrrole,pyrrolidine, pyrroline, 4,5,6,7-tetrahydro-2-indole, tetrahydro-thienyl, tetrazole, thiadiazole, thiazole, thiomorpholine,thiophene, triazole, triazolone or triazole, in which heteroaryl is unsubstituted or substituted once, twice orthree times by identical or different radicals which are derivedfrom the sériés -C(O)-(Ci-C4)-alkyl, -C(O), =0, -NH-(Ci-C4)-alkyl, -NH-((CrC4)-alkyl)2, -(CrCeJ-alkyl, -(CrC8)-alkoxy,halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(CrC4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl,cyano, hydroxycarbonyl, aminocarbonyi, -(Ci-C4)-alkoxycarbonyl,phenyl, phenoxy, benzyl, benzyloxy, -S(O)X-R11, in which x is theinteger zéro, 1 or 2, -O-(CrC4)-alkyl, -C(O)-OH, -C(O)-O-(Ci-C4)-alkyl, -NH-C(O)-(Ci-C4)-alkyl or tetrazolyl, 5. -(Ci-C6)-alkyl in which alkyl is straight-chain or branched and isunsubstituted or substituted once, twice or three times,independently of each other, by 5.1 aryl, in which aryl is defined as above, 5.2 heteroaryl having from 5 to 14 ring members, in whichheteroaryl is defined as above, 012907 10 5.3 -(C3-C6)-cycloalkyl, 5.4 -O-R11, 5.5 =0, 5.6 halogen, 5.7 -CN, 5.8 -cf3, 5.9 -S(O)XR11, in which x is the integer zéro, 1 or 2, 5.10 -C(O)-O-R11, 5.11 -C(O)-N(R11)2, 5.12 -C(O)-R11, 5.13 -N(R11)2, 5.14 a radical of the formula R11 R<JX XR11 or 5.15 a radical of the formula - in which -R11 R11 is a) hydrogen atom, b) (Ci-C6)-alkyl in which alkyl is unsubstituted orsubstituted once, twice or three times by 1. aryl, in which aryl is defined as above, 2. heteroaryl having 5 to 14 ring members, inwhich heteroaryl is defined as above, 3. halogen, 4. -N-(CrC6)n-alkyl, in which n is the integer zéro,1 or 2 and alkyl is unsubstituted or substitutedonce, twice or three times, independently ofeach other, by halogen or by -C(O)-OH, 5. -O-(Ci-Ce)-alkyl or 6. -C(O)-OH, c) aryl, in which aryl is defined as above, or d) heteroaryl having from 5 to 14 ring members, inwhich heteroaryl is defined as above, and in the case of (R11)2, the radical R11 has, independent ofeach other, the meaning of a) to d), Z is 1. aryl in which aryl is defined as above, 012907 11 2. heteroaryl having from 5 to 14 ring members, in which heteroarylis defined as above, 3. -(CrC6)-alkyl, in which alkyl is straight-chain or branched and issubstituted once or twice by phenyl or -OH, 4. -C(O)-O-R11, or 5. -C(O)-N(R11)2, and the other substituents R1, R2, R3 and R4 in each case are, independently ofeach other, 1. hydrogen atom, 2. haiogen, 3. -(CrC4)-alkyl, 4. heteroaryl having from 5 to 14 ring members, in which heteroarylis as defined above, 5. -(CrC6)-alkyl, 6. -NO2, 7. -CN, 8. -O-(C0-C4)-alkyl-aryl, in which aryl is defined as above, 9. -O-(CrC4)-alkyl, 10. -OR11, 11. -N(R11)2, 12. -S(O)X-R11, in which x is the integer zéro, 1 or 2, or 13. -CF3, R5is 1. hydrogen atom, 2. -OH, or 3. =0, and R6is 1. aryl, from the group naphthyl, 1-naphthyl, 2-naphthyl, phenyl,biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl orfluorenyl, in which aryl is unsubstituted or substituted, once, twice or threetimes, by identical or different radicals from the sériés -C(O)-(CrG4)-alkyl, -C(O), =0, -NH-(CrC4)-alkyl, -NH-((C1-C4)-alkyl)2, -(CrC8)-alkyl, -(CrC8)-alkoxy, haiogen, nitro, amino, trifluoromethyl,hydroxyl, -CF3, hydroxy-(Ci-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy,formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(CrC4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)X-R11, inwhich x is the integer zéro, 1 or 2, -O-(CrC4)-alkyl, -C(O)-OH,-C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C1-C4)-alkyl ortetrazolyl, or 012907 12 2. heteroaryl having from 5 to 14 ring members, in which heteroaryl is defined as above and in which heteroaryl is unsubstituted or substituted, once, twice orthree times, by identical or different radicals from the sériés-C(O)-(Ci-C4)-alkyl. -C(O), =0, -NH-(CrC4)-aîkyl, -NH-((CrC4)-alkyl)2, -(CrCsJ-alkyl, -(CrC8)-alkoxyf halogen, nitro, amino,trifluoromethyl, hydroxyl, -CF3, hydroxy-(CrC4)-aIkyl such ashydroxymethyl or 1 -hydroxyethyl or 2-hydroxyethyl,methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,hydroxycarbonyl, aminocarbonyl, -(Ci-C4)-alkoxycarbonyl,phenyl, phenoxy, benzyl, benzyloxy, -S(O)X-R11, in which x is theinteger zéro, 1 or 2, -O-(CrC4)-alkyl, -C(O)-OH,-C(O)-O-(CrC4)-alkyl, -NH-C(O)-(CrC4)-alkyl or tetrazolyl.

The invention furthermore relates to the use, according to the invention, ofthe compound of the formula I, whereE is N atom or the radical -C(R19)-, in which R19 is hydrogen atom, one of the substituents R1, R2, R3 and R4 is a radical of the formula II, inwhich R8 is hydr-ogen atom, R9 is 1. a characteristic radical of an amino acid from the group histidine,serine, tryptophan, threonine, cysteine, méthionine, asparagine,glutamine, lysine, arginine, glutamic acid and aspartic acid, or 2. -(CrC6)-alkyl, in which alkyl is straight-chain or branched and isunsubstituted or substituted, once or twice, by a) phenyl, b) a radical from the group azepine, azetidine, benzimidazole,benzothiazole, benzothiophene, benzoxazole, diazepine,imidazole, indole, isothiazoie, isoxazole, morpholine, 1,3,4-oxa-diazole, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, oxazole piperidine,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,pyrroline, thiazole, thiomorpholine, thiophene or triazole, c) -NH(R11), d) -C(O)-R12, in which R12 is naphthyl, phenyl, morpholinyl or pyrimidinyl, e) -O-R11, f) -N(R12)-phenyl, in which R12 is defined as above, g) -S(O)X-R12, in which x is zéro, 1 or 2, and 012907 13 h) -CN, or i) -(C3-C6)-cycloalkyl, and the radicals defined above by a), b), d) and i) and R12 areunsubstituted or are substituted, once or twice, by -OH, -(C1-Ç4)-alkyl, -CF3, halogen, -O-(Ci-C4)-alkyl, -COOH, -C(O)-O-(CrC4)-alkyl, -NH2 or -NH-C(O)-(CrC4)-alkyl,

Zis 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione,imidazole, imidazolidine, imidazoline, indazole, isothiazole,isothiazolidine, isoxazole, isoxazolidine, 2-isoxazolidine,isoxazolone, morpholine, 1,3,4-oxadiazole, oxadiazolidinedione,oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide, oxazole, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine,pyrazine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyrimidine,tetrazole, thiadiazole, thiazole, thiomorpholine, triazole or triazolone,and the heteroaryl radical is unsubstituted or substituted, once, twiceor three times, independently of each other, by 1.1 -C(O)-R15, in which R15 is hydrogen atom or -(Ci-C4)-alkyl, 1.2 -(CrC4)-alkyl, 1.3 -O-R15, in which R15 is hydrogen atom or -(Ci-C4)-alkyl, 1.4 -N(R15)-R16, in which R15 and R16 are, independently ofeach other, hydrogen atom or -(CrC4)-alkyl, 1.5 halogen, or 1.6 keto radical, 2. -C(O)-R15, in which R15 is hydrogen atom or -(CrC4)-alkyl, 3. -C(O)-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl, or 4. -C(O)-N(R15)-R16, in which R15 and R16 are, independently ofeach other, hydrogen atom or -(CrC4)-alkyl, R11 is 1. -(CrC4)-alkyl, 2. R13 or, 3. -N(R13)2, in which R13 is, independently of each other, a) hydrogen atom, b) -(CrC6)-alkyl, c) -(C1-C4)-alkyl-O-(Ci-C4)-alkyl, d) -(Ci-C6)-alkyl-N(R15)2> in which R15 is defined as above, or e) -(Co-C4)-alkyl which is substituted, once or twice, by imidazolyl, morpholinyl or phenyl, or 012907 14 R8 and R9 form, together with the nitrogen atom and carbon atom to whichthey are in each case bonded, a ring of the formula lia from thegroup pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene,pyridazine, pyrimidine, pyrazine, piperazine, pyrazoie, imidazole,pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole,isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole,thiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, oxadiazolone,isoxazolone, triazolones, oxadiazolidinedione, triazole, which aresubstituted by F, CN, CF3 or COO-(Ci-C4)-alkyl, 3-hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles, 1,3,4-oxadiazole, isothiazolidine,thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline,triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine,indole, tetrahydroquinoline, tetrahydroisoquinoline and isoquinoline,or R9 and Z form, together with the carbon atoms to which they are in eachcase bonded, a ring of the formula Ile from the group pyrrole,pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine,pyrimidine, pyrazine, piperazine, pyrazoie, imidazole, pyrazoline,imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2- isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole,isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole,quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine,pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline,isoquinoline, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides,oxadiazolone, isoxazolone, triazolones, oxadiazolidinedione,triazole, which are substituted by F, CN, CF3 or COO-(C-i-C4)-alkyl, 3- hydroxypyrro-2,4-diones, 1,3,4-oxadiazole and 5-oxo-1,2,4-thiadiazole and the other substituents R1, R2, R3 and R4 in each case are, independently ofeach other, 1. hydrogen atom, 2. halogen, 3. -(CrC4)-alkyl, 4. -CN, 5. -NO2, 6. -0-(Co-C4)-alkyI-phenyl, 7. -O-(C1-C4)-alkyl, 8. -N-(Co-C4)-aIkyl-phenyl, 9. -N-(C1-C4)-a!kyl or 012907 15 1O.-CF3, R5is 1. hydrogen atom, 2. -OH, or 3. =0, and R6 is 1. phenyl, substituted, once or twice, by 1.1 -CN, 1.2 -NO2, 1.3 -O-(Ci-C4)-alkyl, or 1.4 -NH2, or 2. is pyridine or pyrimidine, where pyridine or pyrimidine is unsubstituted or substituted, once,twice or three times, by identical or different radicals from the sériés-C(O)-(CrC4)-alkyl, -C(O), =0, -NH-(CrC4)-alkyl, -NH-((CrC4)-alkyl)2, -(CrCeValkyl, -(Ci-C8)-alkoxy, halogen, nitro, amino,trifluoromethyl, hydroxyl, -CF3, hydroxy-iCrC^-alkyl such ashydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyl, -(Ci-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl,benzyloxy, -S(O)X-R11, in which x is the integer zéro, 1 or 2,-O-(CrC4)-alkyl, -C(O)-OH, -C(O)-O-(Ci-C4)-alkyl, -NH-C(O)-(CrC4)-alkyl or tetrazolyl.

The invention furthermore relates to the use, according to the invention, ofthe compound of the formula I,where E is the radical -C(R19)-, in which R19 is hydrogen atom or R9, one of the substituents R1, R2, R3 and R4 is a radical of the formula II inwhich D is -C(O)-, R8 is hydrogen atom, Z is 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, -C(O)-OH or -C(O)-NH2, R9 is 1. -(Ci-C4)-alkyl, in which alkyl is straight-chain or branched and is substituted once or twice, independently of each other, by 1.1 -S(O)-R11, where R11 is defined as below, 1.2 -N(R11)2, where R11 is defined as below, or 1.3 pyrrole, or 2. the characteristic radical of an amino acid from the grouphistidine, tryptophan, serine, threonine, cysteine, méthionine, 012907 16 asparagine, glutamine, lysine, arginine, glutamic acid andaspartic acid, R11 is a) hydrogen atom, b) -(C-i-Ce)-alkyl, in which alkyl is unsubstituted or substituted, onceor three times, independently of each other, by halogen, or c) phenyl, in which phenyl is unsubstituted or substituted, once tothree times, independently of each other, by halogen or -(C1-C4)-alkyl, the other substituents R1, R2, R3 and R4 are in each case hydrogen atom, R5 is hydrogen atom, and R6 is phenyl, pyridine or pyrimidine, where phenyl, pyridine or pyrimidine is unsubstituted or substituted,once, twice or three times, by identical or different radicals from thesériés -C(O)-(CrC4)-alkyl, -C(O), =0, -NH-(C1-C4)-alkyl, -NH-((Ci-C4)-alkyl)2, -(CrC8)-alkyl, -(Ch-CsJ-alkoxy, halogen, nitro,amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(CrC4)-alkyl such ashydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyi, -(CrC4)-alkoxycarbonyl, phenyl, phenoxy, benzyl,benzyloxy, -S(O)X-R11, in which x is the integer zéro, 1 or 2,-O-(CrC4)-alkyl, -C(O)-OH, -C(O)-O-(C.,-C4)-alkyl, -NH-C(O)-(Ci-C4)-alkyl or tetrazolyl.

The invention furthermore relates to the use, according to the invention, ofthe compound of the formula la

and/or a stereoisomeric form of the compound of the formula la and/or aphysiologically tolerated sait of the compound of the formula la, where 012907 17

E and M are identical or different and are, independently of each other Natom or CH R21 and R31 are identical or different and are, independently of eachother, 1. hydrogen atom, 2. halogen, 3. -(CrC4)-alkyl, 4. -CN, 5. -CF3, 6. -OR15, in which R15 is hydrogen atom or-(CrC4)-alkyl, 7. -N(R15)-R16, in which R15 and R16 are, independently of eachother, hydrogen atom or-(Ci-C4)-alkyI, 8. -C(O)-R15, in which R15 is hydrogen atom or _(CrC4)-alkyl, or 9. -S(O)X-R15, in which x is the integer zéro, 1 or 2, and R15 ishydrogen atom or -(CrC4)-alkyl, R22 is 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione,imidazole, imidazolidine, imidazoline, indazole, isothiazole,isothiazolidine, isoxazole, 2-isoxazolidine, isoxazolidine,isoxazolone, morpholine, oxazole, 1,3,4-oxadiazole,oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyrimidine, tetrazole, thiadiazole,thiazole, thiomorpholine, triazole or triazolone, and the heteroaryl radical is unsubstituted or is substituted once,twice or three fîmes, independently of each other, by 1.1 -C(O)-R15, in which R15 is hydrogen atom or -(CrC4)-alkyl, 1.2 -(CrC4)-alkyl, 1.3 -O-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl, 1.7 -N(R15)-R16, in which R15 and R16 are, independently ofeach other, hydrogen atom or -(Ci-C4)-alkyl, 1.8 halogen, or 1.9 keto radical, 2. -C(O)-R15, in which R15 is hydrogen atom or —(Ci-C4)-aIkyl, 3. -C(O)-OR15, in which R15 is hydrogen atom or -(C1-C4)-alkyl, or 4. -C(O)-N(R17)-R18, in which R17 and R18 are, independently ofeach other, hydrogen atom, -(CrC4)-alkyl-OH, -O-(CrC4)-alkyl or-(CrC4)-alkyl, 012907 18 R23 is hydrogen atom or-(Ci-C4)-alkyl, R24 is 1. a heteroaryl radical from the group pyrrole, furan, thiophene,imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole,tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxa-diazolones, isoxazolones, oxadiazolidinediones, triazoles, 3- hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine,pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine,quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline,β-carboline and benzo fused cyclopenta dérivatives or cyclohexadérivatives of these heteroaryl radicale, where the heteroaryl radical is unsubstituted or is substituted,once, twice or three times, independently of each other, by-(Ci-C5)-alkyl, -(CrC5)-alkoxy, halogen, nitro, amino,trifluoromethyl, hydroxyl, hydroxy-(C-i-C4)-alkyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, amino-carbonyl or -(C-i-C4)-alkoxycarbonyl, or 2. an aryl radical from the group phenyl, naphthyl, 1-naphthyl,2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl and 4- biphenylyl, anthryl or fluorenyl, and the aryl radical is unsubstituted or substituted, once, twice orthree times, independently of each other, by -(CrC5)-alkyl,-(C-|-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl,hydroxy-(C-i-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl,acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(Ci.C4)-alkoxycarbonyl.

The invention furthermore relates to the use, according to the invention, ofthe compound of the formula la, where E and M are identical or different and are, independently of each other, Natom or CH, R21 and R31 are identical or different and, independently of each other,are defined as above under 1. to 9., R22is1. a heteroaryl radical from the group imidazole, isothiazole,isoxazole, 2-isoxazolidine, isoxazolone, 1,3,4-oxadiazoie,oxadiazolidinedione, 1,2,3,5-oxadiazolone, oxazole, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, tetrazole, thiadiazole, thiazole, triazoleor triazolone, and the heteroaryl radical is unsubstituted or issubstituted once, twice or three times, independently of eachother, by 012907 19 1.1 keto radical, 1.2 haiogen or 1.3 -(CrC2)-alkyl, or 2. -C(O)-N(R17)-R18, in which R17 and R18 are, independently ofeach other, hydrogen atom, -(CrC4)-alkyl-OH, -O-(CrC4)-alkyl,or-(CrC4)-alkyl, R23 is hydrogen atom, methyl or ethyl, R24 is 1. a heteroaryl radical from the group of the unsaturated, partiallysaturated or completely saturated rings which are derived frompyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan,thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,triazole or isothiazole, where the heteroaryl radical is unsubstituted or substituted, once,twice or three times, independently of each other, by -(C-1-C4)-alkyl, -(C-i-C4)-alkoxy, F, Cl, J, Br, nitro, amino, trifluoromethyl,hydroxyl, hydroxy-(C-|-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or-(C-]-C4)-alkoxycarbonyl, or 2. phenyl and phenyl is unsubstituted or is substituted once, twiceor three times, independently of each other, by F, Cl, I, Br, CF3,-OH, -(CrC4)-alkyl or -(Ci-C4)-alkoxy.

The invention furthermore relates to the use, according to the invention, ofthe compound N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro- [1,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-y!)-1H-indole-5-carboxamide or N-((S)-1 -carbamoyl-2-diphenylaminoethyl)-2-(2-methyl-aminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamide.

The term “haiogen” is understood as meaning fluorine, chlorine, bromine oriodine. The terms “-(CrCe)-alkyr, “-(CrC6)-alkyr and “-(Ci-C4)-aIkyl” areunderstood as meaning hydrocarbon radicals whose carbon chain isstraight-chain or branched and contains from 1 to 8, from 1 to 6 and from 1to 4 carbon atoms, respectively, such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl, hexyl, heptyl or octyl. The term "-(Co)-alkyl” is understood asmeaning a covalent bond. Examples of cyclic alkyl radicals are 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. 012907 20

The phrase “R8 and R9 form, together with the nitrogen atom and carbonatom to which they are in each case bonded, a heterocyclic ring of theformula lia" is understood as meaning radicals which are derived frompyrrole, pyrroline, pyrrolidine, imidazole, pyrazole, oxazole, isoxazole,tetrazole, isoxazoline, isoxazolidine, morpholine, thiazole, isothiazole,isothiazoline, purine, isothiazolidine, thiomorpholine, pyridine, piperidine,pyrazine, piperazine, pyrimidine, pyridazine, indole, isoindole, indazole,benzimidazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline, pteridine, triazolones, tetrazole, 1,2,3,5-oxathia-diazole-2-oxides, oxadiazolones, isoxazolones, oxadiazolidinediones,triazoles, which are substituted by F, -CN, -CF3 or-C(O)-O-(Ci-C4)-alkyl, 3-hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles, imidazolidine, carbolineand benzofused dérivatives of these heterocycles.

The phrase “R9 and Z form, together with the carbon atoms to which theyare in each case bonded, a heterocyclic ring of the formula Ile” isunderstood as meaning radicals which [lacuna] from the group pyrrole,pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine,pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline,imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine,isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine,thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole,phthalazine, quinazoline, quinoxaline, purine, pteridine, indole,tetrahydroquinoline, tetrahydroisoquinoline, isoquinoline, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, oxadiazolone, isoxazolone, triazolone,3-hydroxypyrro-2,4-diones, 1,3,4-oxadiazole and 5-oxo-1,2,4-thiadiazole,oxadiazolidinedione, triazole, which are unsubstituted or substituted by F,CN, CF3 or C(O)-O-(Ci-C4)-alkyl.

The phrase “heteroaryl radical from the group of the unsaturated, partiallysaturated or completely saturated rings which are derived from pyridine,pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, imidazole,pyrazole, oxazole, isoxazole, thiazole and isothiazole”, is understood asmeaning, for example, compounds such as piperazine, pyrazoline,imidazoline, pyrazolidine, imidazolidine, tetrahydropyridine, isoxazoline,isoxazolidine, morpholine, isothiazoline, isothiazolidine, tetrahydro-1,4-thiazine and piperidine.

The term “aryl” is understood as meaning aromatic hydrocarbon radicalshaving from 6 to 14 carbon atoms in the ring. Examples of-(C6-C-i4)-aryl 012907 21 radicals are phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl,biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryland fluorenyl. Biphenylyl radicals, naphthyl radicals and, in particular,phenyl radicals are preferred aryl radicals. Aryl radicals, in particular phenylradicals, can be substituted once or more than once, preferably once, twiceor three times, by identical or different radicals, preferably by radicals fromthe sériés -(CrC8)-alkyl, in particular -(CrC4)-alkyl, -(CrC8)-alkoxy, inparticular -(Ci-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl,hydroxy-(CrC4)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,hydroxycarbonyl, aminocarbonyl, -(Ci-C4)-alkoxycarbonyl, phenyl,phenoxy, benzyl, benzyloxy and tetrazolyl. The same applies, in acorresponding manner, for example, for radicals such as arylalkyl orarylcarbonyl. Arylalkyl radicals are, in particular, benzyl and also 1- and 2- naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and 9-fluorenylmethyl.Substituted arylalkyl radicals are, for example, benzyl radicals andnaphthylmethyl radicals which are substituted, in the aryl moiety, by one ormore -(CrC8)-alkyl radicals, in particular -(CrC4)-alkyl radicals, forexample 2-, 3- and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl,4-octylbenzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7-and 8-methyl-1 -naphthylmethyl, and 1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl, benzyl radicals and naphthylmethyl radicals which aresubstituted, in the aryl moiety, by one or more -(CrC8)-alkoxy radicals, inparticular -(Ci-C4)-alkoxy radicals, for example 4-methoxybenzyl,4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyland 2,3,4-trimethoxybenzyl, nitrobenzyl radicals, for example 2-, 3- and 4-nitrobenzyl, halobenzyl radicals, for example 2-, 3- and 4-chlorobenzyl, 2-, 3- and 4-fluorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl andtrifluoromethylbenzyl radicals, for example 3- and 4-trifluoromethylbenzyland 3,5-bis(trifluoromethyl)benzyl.

In monosubstituted phenyl radicals, the substituent can be located in the 2position, the 3 position or the 4 position. Doubly substituted phenyl can besubstituted in the 2,3 position, the 2,4 position, the 2,5 position, the 2,6position, the 3,4 position or the 3,5 position. In triply substituted phenylradicals, the substituents can be located in the 2,3,4 position, the 2,3,5position, the 2,4,5 position, the 2,4,6 position, the 2,3,6 position or the 3,4,5position. 012907 22

The commente made with regard to the aryl radicals apply, in acorresponding manner, to divalent arylene radicals, for example tophenylene radicals, which can be présent, for example, as 1,4-phenyIeneor as 1,3-phenylene. Phenylene-(C-i-C6)-a!kyl is, in particular,phenylenemethyl (-C6H4-CH2-) and phenyleneethyl, (CrC6)-alkylenephenyl, in particular methylenephenyl (-CH2-C6H4-). Phenylene-(C2-Ce)-aIkenyl is, in particular, phenyleneethenyl and phenylenepropenyl.

The phrase “heteroaryl having from 5 to 14 ring members” means a radicalof a monocyclic or polycyclic aromatic System having from 5 to 14 ringmembers which contains 1, 2, 3, 4 or 5 heteroatoms as ring members.Examples of heteroatoms are N, O and S. If several heteroatoms areprésent, they may be identical or different. Heteroaryl radicals can also besubstituted,. once or more than once, preferably once, twice or three times,by identical or different radicals from the sériés ~(Ci-Ce)-alkyl, in particular-(CrC^-alkyl, -(CrCgJ-alkoxy, in particular -(C-i-C4)-alkoxy, halogen, nitro,-N(R10)2, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, such ashydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl,acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(CrC4)-alkoxycarbonyl,phenyl, phenoxy, benzyl, benzyloxy and tetrazolyl. Heteroaryl having from5 to 14 ring members is preferably a monocyclic or bicyclic aromatic radicalwhich contains 1, 2, 3 or 4, in particular 1, 2 or 3, identical or differentheteroatoms from the sériés N, O and S, and which can be substituted by1, 2, 3 or 4, in particular 1 to 3, identical or different substituents from thesériés -(CrC6)-alkyl, -(C-i-C6)-alkoxy, fluorine, chlorine, nitro, -N(R10)2,trifluoromethyl, hydroxyl, hydroxy-(CrC4)-alkyl, -(Ci-C4)-alkoxycarbonyl,phenyl, phenoxy, benzyloxy and benzyl. Particularly preferably, heteroarylis a monocyclic or bicyclic aromatic radical having from 5 to 10 ringmembers, in particular a 5-membered to 6-membered monocyclic aromaticradical which contains 1, 2 or 3, in particular 1 or 2, identical or differentheteroatoms from the sériés N, O and S and which can be substituted by 1or 2 identical or different substituents from the sériés -(CrC4)-alkyI,halogen, hydroxyl, -N(R10)2, -(CrC4)-alkoxy, phenyl, phenoxy, benzyloxyand benzyl.

The term "heterocycle having from 5 to 12 ring members” means amonocyclic or bicyclic 5-membered to 12-membered heterocyclic ringwhich is partially saturated or completely saturated. Examples ofheteroatoms are N, O and S. The heterocycle is unsubstituted or is 012907 23 substituted by identical or different substituents at one or mofe carbonatoms or at one or more heteroatoms. These substituents hâve beendefined above in connection with the heteroaryl radical. In particular, theheterocyclic ring is substituted at carbon atoms, once or more than once,for example once, twice, three times or four times, by identical or differentradicals from the sériés -(Ci-C8)-alkyl, for example -(Ci-C4)-alkyl, -(CrC8)-alkoxy, for example ~(CrC4)-alkoxy, such as methoxy, phenyl-(CrC4)-alkoxy, for example benzyloxy, hydroxyl, oxo, halogen, nitro, amino ortrifluoromethyl and/or is substituted at the ring nitrogen atom(s) in theheterocyclic ring by -(CrC8)-alkyl, for example -(Ci-C4)-alkyl such asmethyl or ethyl, by optionally substituted phenyl or phenyl-(C-i-C4)-alkyl, forexample benzyl. Nitrogen heterocycles can also be présent as N-oxides oras quaternary salts.

Examples of the terms heteroaryl having from 5 to 14 ring members andheterocycle having from 5 to 12 ring members are radicals which arederived from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole,isoxazole, thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides,triazolones, oxadiazolones, isoxazolone, oxadiazolidinedione, triazole,which are substituted by F, -CN, -CF3 or -C(O)-O-(Ci-C4)-alkyl, 3- hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine,pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline,quinoxaline, quinazoline, cinnoline, -carboline and benzo fused, cyclopentafused, cyclohexa fused or cyclohepta fused dérivatives of theseheterocycles. Particular preference is given to the radicals 2- or 3-pyrrolyl,phenylpyrrolyl, such as 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4- imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl,1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide,2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl,for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or-3-indolyl, 4,5,6,7-tetrahydro-2-indolyl,cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl,1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzo-thienyl, 2-benzoxazolyl or benzothiazolyl or dihydropyridinyl, pyrrolidinyl, forexample 2- or 3-(N-methylpyrrolidinyl), piperazinyl, morpholinyl,thiomorpholinyl, tetrahydrothienyl and benzodioxolanyl.

The general structural formula of α-amino acids is as follows: □12907 24

R\H C—COOH/

H_N t

The α-amino acids differ from each other in the radical R which, within thecontext of the présent application, is designated the “characteristic radical”of an amino acid. When R9 dénotés the characteristic radical of amino acid,use is preferably made of the characteristic radicals of the followingnaturally occurring α-amino acids: glycine, alanine, valine, leucine,isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine,méthionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acidand aspartic acid. Particular preference is given to histidine, tryptophan,serine, threonine, cysteine, méthionine, asparagine, glutamine, lysine,arginine, glutamic acid and aspartic acid. In addition, amino acids which donot occur naturally, such as 2-aminoadipic acid, 2-aminobutyric acid, 2- aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid,1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroiso-quinoline-3-carboxylic acid, 2-aminopimellic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoicacid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine,alloisoleucine, allothreonine, allohydroxylysine, 4-hydroxyproline, 3- hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocystéine, homocysteic acid, homotryptophan,cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine,2-amino-3-phenylaminopropionic acid, 2-amino-3-phenylaminoethyl-propionic acid, phosphinothricin, 4-fIuorophenylalanine, 3-f!uorophenyl-alanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenyl-alanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenyl-alanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluoro-tryptophan, 5-methoxytryptophan, méthionine sulfone, méthionine sulfoxideor -NH-NR11-C(O)N(R11)2, which are also substituted, where appropriate,are also preferred characteristic radicals of amino acid which are employedas the radical R8. When amino acids which occur naturally, and also aminoacids which do not occur naturally, possess a functional group such asamino, hydroxyl, carboxyl, mercapto, guanidyl, imidazolyl or indolyl, thisgroup can also be protected. 012907 25

The N-protecting groups which are customary in peptide chemistry, forexample protecting groups of the urethane type, benzyloxycarbonyl (Z),t-butyloxycarbonyl (Boc), 9-fluorenyloxycarbonyl (Fmoc), allyloxycarbonyl(Aloc), or of the acid amide type, in particular formyl, acetyl ortrifluoroacetyl, and also of the alkyl type, for example benzyl, are preferablyused as suitable protecting groups for this purpose. When an imidazoleradical is présent in R8, the sulfonic acid dérivative of the formula IV, whichis employed for the sulfonamide formation, serves, for example, as thegroup for protecting the imidazole nitrogen, which group can be eliminatedonce again in the presence of bases such as sodium hydroxide.

The compounds of the formulae I, la and Ib are prepared as described inpatent applications WO 01/00610 and WO 01/30774. The startingcompounds for the Chemical reactions are known or can be readilyprepared using methods known from the literature.

Due to the pharmacological properties, which are évident in the modelsemployed, of the ΙκΒ-kinase inhibitors which are used in accordance withthe invention, said inhibitors are suitable for being employed in ail forms ofpain, in particular in association with pains in which inflammatory processesplay a rôle.

The pharmaceuticals according to the invention can be administered orally,by inhalation, rectally or transdermally or by means of subcutaneous,intraarticular, intraperitoneal or intravenous injection. Oral or intraarticularadministration is preferred.

The invention also relates to a process for producing a pharmaceuticalwhich comprises bringing at least one compound of the formulae I or la,together with a pharmaceutically suitable and physiologically toleratedexcipient and, where appropriate, other suitable active compounds,additives or auxiliary substances, into a suitable form for administration.

Examples of suitable solid or galenic préparation forms are granules,powders, sugar-coated tablets, tablets, (micro)capsules, suppositories,syrups, juices, suspensions, émulsions, drops or injectable solutions, andalso préparations with protracted active compound release, in thepréparation of which customary auxiliary substances, such as carriersubstances, disintegrants, binders, coating agents, swelling agents, 012907 26 glidants or lubricants, flavorings, sweeteners and solubilizers are used.Frequently employed auxiliary substances which may be mentioned aremagnésium carbonate, titanium dioxide, lactose, mannitol and othersugars, talc, milk protein, gelatin, starch, cellulose and its dérivatives, 5 animal and vegetable oils, such as cod liver oil, sunflower oil, groundnut oilor sesame oil, polyethylene glycol and solvents, such as stérile water andmonohydric or polyhydric alcohols, such as glycerol. The pharmaceuticalpréparations are preferably produced and administered in dosage units,with each unit containing as the active constituent a particular dose of the 10 compound of the formula I according to the invention. In the case of soliddosage units, such as tablets, capsules, sugar-coated tablets orsuppositories, this dose can be up to about 1000 mg, preferably from about50 mg to 300 mg, and, in the case of injection solutions in ampoule form,up to about 300 mg, preferably from about 10 mg to 100 mg. Depending on 15 the activity of the compound according to the formulae I or la, daily dosesof from about 20 mg to 1000 mg of active compound, preferably of fromabout 100 mg to 500 mg, are indicated for treating an adult patient of about70 kg in weight. However, higher or lower daily doses may also possibly beappropriate. The daily dose can be administered either by means of a 20 once-only administration in the form of a single dosage unit, or of severalsmaller dosage units, or by means of the multiple administration ofsubdivided doses at predetermined intervals.

As a rule, mass-spectroscopic methods (FAB-MS, ESI-MS) are used for 25 determining end products. Températures are given in degrees centigrade;RT dénotés room température (from 22°C to 26°C). Abbreviations whichare used are either explained or correspond to the customary conventions.The invention is explained in more detail below with the aid of examples. 27

Préparation Examples A.1.) Synthesis of the amino acid (methyl (S)-2-amino-3-diphenylaminopropionate (5))

N-Benzyloxycarbonyl-L-serine-p-lactone (2) 54.8 g (0.209 mol) of triphenylphosphine were suspended in 600 ml ofacetonitrile and the mixture was cooled down to -35°C to -45°C whileexcluding moisture. 36.4 g (0.209 mol) of diethyl azodicarboxylate wereadded dropwise at this température within the space of 50 minutes. Themixture was subsequently stirred at -35°C for 15 minutes. A solution of50 g (0.209 mol) of N-benzyloxycarbonyl-L-serine (1) in 500 ml ofacetonitrile was then slowly added dropwise to this mixture such that thetempérature did not rise above -35°C. The mixture was then stirred at 5°Cfor 12 h. In order to terminate the reaction, the reaction solution was freedfrom the solvent under reduced pressure and the crude product waspurified by means of medium-pressure chromatography on silica gel.(DCM/AcCN: 25/1). 20.8 g of N-benzyloxycarbonyl-L-serine-p-lactone (2)were obtained after the solvent had been removed; yield 45%; (see alsoOrg. Synth. 1991 (70) 1ff.) in fine needles.

Empirical formula CnHiiNO4; M.W. = 221.2; MS (M+H) 222.1; 1H NMR(DMSO-de) 4.30 (m, 1H), 4.45 (m, 1H), 5.10 (s, 2H), 5.22 (m, 2H), 7.45 (m,5H), 8.20 (d, J = 9.8 Hz, 1H). (S)-2-Benzyloxycarbonylamino-3-diphenylaminopropionic acid (3) 012907 28 5.0 g (22.6 mmol) of serine lactone (2) were mixed by stirring with 20 g(118.2 mmol) of diphenylamine, and the mixture was heated at 100°C for2 h. The crude product was purified by means of medium-pressurechromatography on silica gel. (DCM/methanol; 9/1, then EA/n-heptane:4/1). 3.65 g (yield 42%) of pure 2-benzyloxycarbonylamino-3- diphenylaminopropionic acid (3) were obtained after the solvent had beenremoved.

Empirical formula C23H22N2O4; M.W. = 390.44; MS (M+H) 391.2; 1H NMR (DMSO-de) 3.85 (m, 1H), 4.18 (m, 1H), 4.3 (m, 1 H), 4.9 (m, 2H), 6.9 (m, 5H), 7.25 (m, 10H).

Methyl (S)-benzyloxycarbonylamino-3-diphenylaminopropionate (4) 6.5 ml (89.1 mmol) of thionyl chloride were added dropwise, at -5°C, to75 ml of methanol and the mixture was stirred for 15 min. 3.6 g (9.22 mmol)of 2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (3), dissolvedin 75 ml of methanol, were then added and the mixture was stirred at roomtempérature for a further 3 hours (h). After the solvents had beenevaporated, the residue was taken up in ethyl acetate and extracted withsodium carbonate solution. The purification by means of flashchromatography (n-heptane/ethyl acetate 7:3) yielded 2.76 g (50% yield) ofmethyl 2-benzyloxycarbonylamino-3-diphenylaminopropionate (4).

Empirical formula C24H24N2O4; M.W. = 404.47; MS (M+H) 405.2; 1H NMR (DMSO-de) 3.58 (s, 3H), 3.95 (m, 1H), 4.18 (m, 1H), 4.4 (m, 1H), 4.95 (m, 2H), 6.9 (m, 6H), 7.3 (m, 9H), 7.85 (d, J = 9.8 Hz, 1H).

Methyl (S)-2-amino-3-diphenylaminopropionate (5)

In order to eliminate the Z protecting group, 2.7 g (6.68 mmol) of the Z-protected dérivative (4) were dissolved in 500 ml of methanol, and 100 mgof catalyst (10% Pd(OH)2-C) were supplied under a protective atmosphèreof nitrogen. The inert gas was subsequently displaced with a large excessof hydrogen and the mixture was shaken for 2 h in the hydrogenatmosphère. In order to terminate the reaction, the catalyst was filtered offand the filtrate was concentrated. 1.65 g (yield: 91%) of methyl 2-amino-3-diphenylaminopropionate (5) were obtained.

Empirical formula C1eH18N2O2; M.W. = 270.32; MS (M+H) 271.2; 1H NMR (DMSO-de) 3.45 (s, 3H), 3.58 (m, 1H), 3.8 (m, 1H), 3.95 (m, 1H), 6.9 (m, 6H), 7.3 (m, 4H). 012907 29 A.2.) Synthesis of the heterocyclic parent substance (2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid (10))

1 -Dimethylamino-4,4-dimethoxypent-1 -en-3-one (8) 100 g (0.76 mol) of 3,3-dimethoxy-2-butanone were stirred, at 120°C for48 h, with 90.2 g of Ν,Ν-dimethylformamide dimethylacetal (0.76 mol). Themethanol which was formed during the reaction was continuously removedfrom the reaction solution by distillation. When the solution was cooled,spontaneous crystallization occurred, with this crystallization being broughtto completion by adding a little heptane. This resulted in 128.24 g of crudeproduct 8 (yield 90%), which was subjected to reaction without any furtherpurification.

Empirical formula C9Hi7NO3; M.W. = 187.24; MS (M+H) 188.2; 1H NMR (DMSO-de) 1.22 (s, 3H), 2.80 (s, 3H), 3.10 (s, 9H), 5.39 (d,J = 15 Hz, 1H), 7.59 (d, J = 15 Hz, 1H).

[4-(1,1 -Dimethoxyethyl)pyrimidin-2-yl]methylamine (9) 1.22 g (53 mmol) of sodium were dissolved in 100 ml of absolute éthanol. 5.8 g (53 mmol) of methylguanidine hydrochloride and 10 g (53 mmol) of 1-dimethylamino-4,4-dimethoxypent-1-en-3-one (8) were added, with stirring,to this solution, which was heated at boiling heat for 4 h. In order toterminate the reaction, the éthanol was evaporated. The product 9, whichwas obtained in this way, was used for the subséquent reaction without anyfurther purification. Yield 11.5 g (58 mmol, quantitative).

Empirical formula C9H15N3O2; M.W. = 197.24; MS (M+H) 198.2; 1H NMR (DMSO-de) 1-45 (s, 3H), 2.78 (s, 3H), 3.10 (s, 6H), 6.75 (d,J = 3 Hz, 1H), 7.0-7.1 (s(b), 1H), 8.30 (d, J = 3 Hz, 1H). 10 10 15 15 20 20 30 012907 2-(2-Methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylic acid (10) 5 g (25 mmol) of [4-(1,1-dimethoxyethyl)pyrimidin-2-yI]methylamine (9) and3.85 g of 4-hydrazinobenzoic acid were added, while stirring, to 150 ml of50% sulfuric acid, and the mixture was heated at 130°C for 4 h. Themethanol which was formed during the reaction was removed continuouslyfrom the reaction solution by distillation. After it had been cooled down to10°C, the reaction mixture was poured onto 200 ml of ice, and the pH wasadjusted to about 5.5 using concentrated sodium hydroxide solution. Theprecipitate of sodium sulfate and product mixture which was formed in thisconnection was filtered off and the filter residue was extracted severaltimes with methanol. The combined methanol extracts were concentratedand the product was purified by means of flash chromatography(DCM/methanol 9:1). Yield: 0.76 g (11%).

Empirical formula C14Hi3N4O2; M.W. = 268.28; MS (M+H) 405.2; 1H NMR(DMSO-de) 2.95 (s, 3H), 6.90-7.10 (s(b), 1 H), 7.18 (d, J = 3 Hz, 1H), 7.4 (s,1H), 7.58 (d, J = 4.5 Hz, 1H), 7.80 (d, J = 4.5 Hz, 1H), 8.30 (s, 1H), 7.80 (d,J = 4.5 Hz, 1H), 8.38 (d, J = 3 Hz, 1H), 11.85 (s, 1H), 12.40-12.60 (s(b),1H). A.3.) Bringing the building blocks together and synthesizing N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)ethyl]-(2%2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (13))

11 N

N / /

! H,N

O

N /

N / 12 13 012907 31 3-Diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carbonyl]-(S)-amino)propionic acid (11) 5.0 g (18.64 mmol) of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid (10) were dissolved in 1.21 of DMF, after which 7.9 g(24.08 mmol) of TOTU and 7.9 ml (46.45 mmol) of ethyldiisopropylaminewere added consecutively. The mixture was stirred at 5°C for 20 min, afterwhich 0.73 g (3.28 mmol) of (S)-2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (5) was added to the solution. After 15 h ofstirring, the mixture was concentrated under reduced pressure, after whichthe residue was taken up in n-butanol and the organic phase was extractedwith a saturated solution of sodium hydrogen carbonate in order toseparate off byproducts. After the organic phase had been dried withMgSO4 and concentrated, the methyl ester of the title compound wasisolated by means of flash chromatography on silica gel (DCM:MeOH =19:1). Yield: 4.3 g (98%)

Empirical formula C30H28N6O3; M.W. = 520.22; MS (M+H) 521.3; 1H NMR (DMSO-d6) 2.95 (s(b), 3H), 3.60 (s, 3H), 4.19-4.58 (m, 2H), 4.85(q, 1H), 6.90-7.10 (m, 7H), 7.18 (d, J = 3 Hz, 1H), 7.25-7.40 (m, 5H), 7.50(d, J = 4.5 Hz, 1H), 7.65 (d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 8.35 (d, J = 3 Hz,1H), 8.70 (d, J = 3.75 Hz, 1H), 11.85 (s, 1H). N-((S)-2-Diphenylamino-1-hydrazinocarbonylethyl)-2-(2- methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (12) 1.0 g (1.92 mmol) of 3-diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carbonyl]-(S)-amino}propionic acid (11) was dissolved in 10 mlof methanol, after which 0.48 g (9.95 mmol) of hydrazine hydrate wasadded and the mixture was stirred at room température for 15 h. Theprecipitate of the product (0.3 g) was separated off from the mother liquorby filtration. Further hydrazone 12 (0.1 g) was isolated from theconcentrated mother liquor by flash chromatography on silica gel(DCM:MeOH = 19:1). Yield: 0.4 g (40%)

Empirical formula C29H28N8O2; M.W. = 520.6; MS (M+H) 521.4; 1H NMR (DMSO-de) 2.95 (s(b), 3H), 4.02-4.58 (m, 2H), 4.4 (s, 2H), 4.85 (q,1 H), 6.90-7.10 (m, 7H), 7.18 (d, J = 3 Hz, 1 H), 7.20-7.45 (m, 5H), 7.50 (d,J =4.5 Hz, 1H), 7.62 (d, J = 4.5 Hz, 1H), 7.99 (s, 1H), 8.25 (d, J = 3 Hz,1 H), 8.35 (s(b), 1 H), 9.30 (s, 1 H), 11.70 (s, 1 H). N-[(S)-2-Diphenylamino-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazoI-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (13) 32 200 mg (0.384 mmol) of N-((S)-2-diphenylamino-1-hydrazinocarbonylethyl)-2-(2-methyiaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (12) weresuspended in 20 ml of methylene chloride, and a 20% solution of phosgenein toluene (0.398 mmol) was added dropwise at 0°C and while stirring. Themixture was stirred at room température for a further 15 h and the solventwas concentrated. The oxadiazolone 13 was subsequently isolated by flashchromatography on silica gel (DCM:MeOH = 9:1). Yield: 160 mg (76%)Empirical formula C30H26N8O3; M.W. = 546.6; MS (M+H) 547.3; 1H NMR (DMSO-de) 2.95 (s(b), 3H), 4.02-4.58 (m, 2H), 4.85 (q, 1H), 6.90- 7.10 (m, 7H), 7.15 (d, J = 3 Hz, 1H), 7.20-7.40 (m, 6H), 7.52 (d, J = 4.5 Hz,1 H), 7.68 (d, J = 4.5 Hz, 1 H), 8.10 (s, 1 H), 8.92 (d, J = 3 Hz, 1 H), 11.78 (s,1H), 12.15-12.40 (s(b), 1H). B.) Example benzimidazole ΙκΒ-kinase inhibitor B.1.) Synthesis of the amino acid (methyl (S)-2-amino-3- diphenylaminopropionate (5)) as described under A.1. B.2.) Synthesis of the heterocyclic parent substance (2-(2- methyIaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid (19))

4-Dimethylamino-1,1-dimethoxybut-3-en-2-one (16) 300 g (307 ml, 2.54 mol) of methylglyoxal dimethylacetal were stirred, at110°C for 4 hours (h), with 303 g (337 ml, 2.54 mol) of N,N-dimethylformamide dimethylacetal. The methanol which was formed duringthe reaction was removed continuously from the reaction solution bydistillation. After having been cooled down, the solution was extracted with 012907 33 heptane and the solvents were evaporated. This resulted in 303 g of crudeproduct 16 (yield 70%), which was reacted without any further purification.Empirical formula CBH15NO3; M.W. = 173.21; MS (M+H) 174.1; 1H NMR (DMSO-d6) 2.10 (s, 1H), 2.80 (s, 3H), 3.10 (s, 3H), 3.25 (s, 3H), 3.3 (s, 3H), 4.42 (s, 1 H), 5.19 (d(b), J = 12.8 Hz, 1H), 7.60 (d, J = 15 Hz,1H). (4-Dimethoxymethylpyrimidin-2-yl)methylamine (17) 0.33 g (14.4 mmol) of sodium was dissolved in 50 ml of absolute éthanol.1.57 g (14.4 mmol) of methylguanidine hydrochloride and 2.48 g(14.4 mmol) of 4-dimethylamino-1,1-dimethoxybut-3-en-2-one (16) wereadded, while stirring, to the solution, which was heated at boiling heat for3 h. In order to terminate the reaction, the éthanol was evaporated. Theresulting product 17 was used without any further purification. Yield: 2.6 g(quantitative).

Empirical formula CBH-i3N3O2; M.W. = 183.21; MS (M+H) 184.1; 1H NMR (DMSO-dé) 2.78 (s, 6H), 3.10 (s, 3H), 5.02 (s, 1H), 6.62 (d,J = 3 Hz, 1 H), 8.30 (d, J = 3 Hz, 1 H). 2-Methylaminopyrimidine-4-carbaldehyde (18) 10 g (54 mmol) of (4-dimethoxymethylpyrimidin-2-yl)methylamine (17) weredissolved in 54 ml of 2N sulfuric acid and the solution was heated at 80°Cfor 3 h while being stirred. After the reaction had cooled down, the reactionsolution was carefully brought to a pH of about 9 using solid Na2CO3 andextracted 3 times with éthanol. After the solvent had been evaporated, thecombined dried extracts yielded the title aldéhyde 18 in 60% yield (4.47 g)Empirical formula CeH7N3O; M.W. = 137.12; MS (M+H) 138.2; 1H NMR (DMSO-de) 2.60-2.80 (s(b), 3H), 6.95 (d, J = 3 Hz, 1H), 7.40-7.60(s(b), 1H), 8.55 (d, J = 3 Hz, 1H). 2-(2-Methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid (19) 4.3 g (31.3 mmol) of methylaminopyrimidine-4-carbaldehyde (18) and 4.8 g(31.1 mmol) of 3,4-diaminobenzoic acid were heated at 150°C for 2 h in300 ml of nitrobenzene. After the mixture had been cooled down to 0°C, theprecipitate of the benzimidazole was separated off from the nitrobenzeneby filtration and the product was purified by flash chromatography(DCM/methanol 4:1). Yield: 2.66 g (32%)

Empirical formula C13H11N5O2; M.W. = 269.28; MS (M+H) 270.2; 012907 34 1H NMR (DMSO-ds) 2.95 (s, 3H), 7.50 (d, J = 3 Hz, 1H), 7.75 (d,J = 4.5 Hz, 1 H), 7.90 (d, J = 4.5 Hz, 1 H), 8.35 (s, 1 H), 8.55 (d, J = 3 Hz,1 H), 8.70-9.05 (s(b), 1H). . .3.) Bringing the building blocks together and synthesizing N-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methyiaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamide (22)

3-Diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carbonyl]-(S)-amino}propionic acid (21) 2.6 g (9.6 mmol) of 2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxylic acid (20) were dissolved in 300 ml of DMF, after which 3.17 g(9.6 mmol) of TOTU and 1.6 ml (11.6 mmol) of ethyldiisopropylamine wereadded consecutively. The solution was stirred at 5°C for 20 min, after which 2.6 g (9.6 mmol) of (S)-2-benzyloxycarbonylamino-3-diphenylamino-propionic acid (5) were added to it. After 16 h of stirring, the mixture wasconcentrated under reduced pressure, after which the methyl ester 21 wasisolated by means of flash chromatography on silica gel (DCM:MeOH =9:1). Yield: 1.61 g (32%)

Empirical formula C29H27N7O3; M.W. = 521.58; MS (M+H) 522.3; 1H NMR (DMSO-de) 2.95 (s(b), 3H), 3.60 (s, 3H), 4.19-4.40 (m, 2H), 4.90(q, 1H), 6.90-7.10 (m, 6H), 7.25-7.35 (m, 6H), 7.40 (d, J = 4.5 Hz, 1H),7.60-7.80 (d(b) 1H), 8.05-8.25 (d(b), 1H), 8.45 (d, J = 3 Hz, 1H), 8.90 (s(b),1H), 11.85 (s(b), 1H). 012907 35 N-((S)-1-Carbamoyl-2-diphenylaminoethyl)-2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide (22) 50 ml of (absolute) methanol were saturated with ammonia at 0°C. 0.5 g(0.959 mmol) of 3-diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carbonyl]-(S)-amino}propionic acid (21) was added to thismixture and the whole was stirred at room température for 24 h. After thesolvent and excess ammonia had been evaporated, the amide 22 wasisolated by flash chromatography on silica gel (DCM:MeOH = 19:1).Yield: 0.43 g (89%)

Empirical formula C29H28N8O2; M.W. = 506.57; MS (M+H) 507.2; 1H NMR (DMSO-de) 2.95 (s(b), 3H), 4.02-4.35 (m, 2H), 4.85 (q, 1H), 6.80- 7.10 (m, 6H), 7.15-7.25 (m, 5H), 7.40 (d, J = 4.5 Hz, 1H), 7.58 (s(b), 1H),7.68 (s(b), 1H), 8.06-8.19 (d(b), 1H), 8.40-8.58 (m, 2H), 13.10 (s, 1H).

Pharmacological examples ΙκΒ-kinase ELISA:

The activity of the ΙκΒ-kinase was determined using an ELISA whichcomprised a biotinylated substrate peptide, which contained the amino acidsequence in the IkB protein from serine 32 to 36, and a spécifie polyclonalor monoclonal antibody (e.g. from New England Biolabs, Beverly, MA,USA, Cat.: 9240), which only bound to the phosphorylated form of the IkBpeptide. This complex was immobilized on an antibody-binding (protein A-coated) plate and detected using a conjugate composed of a biotin-bindingprotein and HRP (e.g. streptavidin-HRP). The activity was quantified withthe aid of a standard curve constructed using substrate phosphopeptide.

Implémentation:

In order to obtain the kinase complex, 10 ml of HeLa S3 cell extract S100were diluted with 40 ml of 50 mM HEPES, pH 7.5, brought to 40% withrespect to ammonium sulfate and incubated on ice for 30 minutes. Theprecipitated pellet was dissolved in 5 ml of SEC buffer (50 mM HEPES,pH 7.5, 1 mM DTT, 0.5 mM EDTA, 10 mM 2-glycerophosphate),

centrifuged at 20 000 g for 15 minutes and filtered through a 0.22 pm filter.The sample was loaded onto a 320 ml Superose-6 FPLC column(Amersham Pharmacia Biotech AB, Uppsala, Sweden) which had beenequilibrated with SEC buffer and which was operated at 4°C with a flowrate of 2 ml/min. The fractions which were located at the migration time ofthe 670 kDa molecular weight standard were combined for the activation.Activation was achieved by means of a 45-minute incubation with 100 nM

36 ΜΕΚΚ1Δ, 250 μΜ MgATP, 10 mM MgCI2, 5 mM dithiothreitol (DTT), 10 mM2-glycerophosphate and 2.5 μΜ microcystin-LR at 37°C. The activatedenzyme was stored at -80°C. The test substances (2 μΙ), which weredissolved in DMSO, were preincubated, at 25°C for 30 minutes, with 43 μΙof activated enzyme (diluted 1:25 in reaction buffer 50 mM HEPES, pH 7.5,10 mM MgCI2, 5 mM DTT, 10 mM β-glycerophosphate, 2.5 μΜmicrocystin-LR). 5 μΙ of substrate peptide (biotin-(CH2)6-DRHDSGLDSMKD-CONH2) (200 μΜ) were then added, after which themixture was incubated for one hour and the reaction was stopped with150 μΙ of 50 mM HEPES, pH 7.5, 0.1% BSA, 50 mM EDTA, antibody[1:200]. 100 μΙ of the stopped reaction mixture or of a standardphosphopeptide dilution sériés (biotin-(CH2)6-DRHDS[PO3]GLDSMKD-CONH2) were then transferred to a protein A plate (Pierce Chemical Co.,Rockford, IL, USA), after which the plate was incubated for 2 hours whilebeing shaken. After 3 washing steps with PBS, 100 μΙ of 0.5 μg/mlstreptavidin-HRP (horseradish peroxidase) (diluted in 50 mM HEPES/0.1%BSA) were added for 30 minutes. After 5 washing steps with PBS, 100 pLof TMB substrate (Kirkegaard &amp; Perry Laboratories, Gaithersburg, MD,USA) were added and the color development was stopped by adding100 pL of 0.18 M sulfuric acid. The absorption was measured at 450 nm.The standard curve was produced by linear régression corresponding to a4-parameter dose-effect relationship. This standard curve was used toquantify the enzyme activity or its inhibition by the test substances.

The IC50 for N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1H-indo!e-5-carboxamide was0.050 μΜ.

The IC50 for N-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide was 0.045 μΜ.

Pain assay

The analgésie and antinociceptive activity of the compound N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1,3,4]oxadiazoI-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide, termed compound13 in that which follows, was demonstrated in the two following models: 1st model: Zymosan-induced paw inflammation in the rat; 012907 37

Parameter: paw withdrawal time or paw withdrawal threshold duringthermal or mechanical stimulation of the hind paw. 2nd model: Kaolin/carrageenan-induced knee joint inflammation in the rat;Parameter. reaction of spinal neurons during pressure stimulation ofthe knee.

Model 1

Experimental implémentation: in short-term anesthésia using isoflurane,1 mg of Zymosan (as a suspension in 100 μΙ of PBS (phosphate-bufferedsait solution)) was injected subcutaneously into the middle of the plantarside of one of the experimental animal’s hind paws. After that, two differentbehavioral tests were used to quantitatively détermine the development ofa hyperalgesia. a) Determihing the paw withdrawal time during thermal stimulation(Hargreaves test).

The experimental animal was placed in a transparent plastic chamberhaving a glass floor. As soon as the experimental animal was no longermoving, following the reconnaissance phase (about 5 min), an infrared lightsource was positioned directly below the hind paw to be stimulated andswitched on. The lamp emitted focused infrared light of increasing intensity,such that the skin température of the hind paw increased almost linearty.As soon as the animal withdrew the paw, the lamp switched itself off. Thetempérature of the paw at the time it is withdrawn has just becomeunpleasant for the animal; this is referred to as the thermal pain threshold. b) Determining the paw withdrawal threshold during mechanicalstimulation (von Frey test)

The experimental animal was placed in a transparent plastic chamberwhose floor consisted of wire-gauze. Punctate pressure of defined strengthwas produced using calibrated nylon fibers, what are termed von Freyhairs. The weakest pressure stimulation during which the animal withdrewits paw détermines the mechanical pain threshold.

About half an hour before, and at various times after, the Zymosaninjection, the thermal and mechanical pain thresholds were determined onthe right hind paw and on the left hind paw (see Tables 1, 2). The decreasein the ipsilateral pain threshold, expressed in % of the contralatéral painthreshold, was then calculated (see Tables 1, 2). The degree ofhyperalgesia is directly proportional to the magnitude of this decrease. 012907 38 ln a control group, the Zymosan injection induced pronounced mechanicaland thermal hyperalgesia (see control data in Tabs. 1 and 2). In anothergroup of animais, which were under short-term isoflurane anesthésia, theabovementioned compound 13 was injected intraperitoneally (i.p.) (in each 5 case 30 mg/kg in polyethylene glycol/water mixture (PEG/water 1:1) about15 minutes before, and 2.5 and 5.5 hours after Zymosan injection. Fromtwo hours after Zymosan injection onward, the thermal hyperalgesia wasless pronounced in these animais than it was in the control group; after thethird administration of the substance, it was no longer possible to observe 10 any side différence at ail in the paw withdrawal time (Tab. 1). In addition,this effect still persisted for 18hrs after the last administration of thesubstance.

Compound 13 also significantly reduced the mechanical hyperalgesia. Theeffect set in 1 hour after Zymosan injection and also still persisted 18 hrs 15 after the last administration of the substance (see Tab. 2).

The activity of compound 13 is very strong in both test models.Comparative data from a study which was carried out previously show thatcompound 13 reduces the thermal hyperalgesia considerably more 20 powerfully than does the NSAID diclofenac.

Table 1: Change in the paw withdrawal time (%)

Time (h) Mean value SD compound Mean value after Zymosan Compound 13 13 control SD control injection (0) Baseline -0.5 0.0 0.0 0.0 0.0 0.5 -16.6 6.6 -21.4 6.3 1 -31.3 14.1 -28.8 11.6 2 -30.2 15.4 -44.8 19.1 3 -15.3 5.3 -49.2 17.9 4 -16.0 11.5 -50.6 23.0 5 -9.7 18.6 -46.6 24.8 6 5.0 2.6 -38.4 17.6 7 3.4 5.8 -29.9 22.1 24 -3.8 7.0 -46.1 18.4 012907 39

Table 2:

Change in the paw withdrawal threshold (%)

Time (h)after Zymosan SD Mean value SD control Mean value compound injection (0) Compound 13 13 control Baseline -0.5 0.0 0.0 0.0 0.0 0.5 -37.4 6.6 -48.9 31.3 1 -43.1 20.5 -66.0 23.2 2 -36.0 17.8 -71.8 26.0 3 -35.1 13.1 -60.5 20.2 4 -46.7 11.9 -64.3 18.2 5 -40.6 14.0 -55.5 25.8 6 -33.1 23.3 -57.3 18.0 7 -44.7 21.5 -47.1 23.9 24 -9.7 26.6 -41.5 17.3

Model 2,

Experimental implémentation: In rats which were under sodium thiopentalanesthésia, the spinal canal was opened and spinal medullary neuronswhich processed the “pain impulses” from the knee-joint were identified.Following identification, a long-term recording, in which the activity of thenerve cell was recorded before and during the development of an acuteinflammation in the knee-joint, was carried out. For this, the responses tonon-noxious and noxious stimulation at the knee-joint were measured in acontrol period before inducing the inflammation and for several hours afterinducing the inflammation.

The acute inflammation was induced by the intraarticular injection of asuspension (about 150 μΙ) of kaolin and carrageenan. In controlledexperiments, only the vehicle was applied to the spinal medullary surface inorder to represent the development of the hyperexcitability under controlconditions. As a rule, this development of hyperexcitability took place within2 to 4 hours and was expressed in a marked increase in the responses tonon-noxious and noxious stimulation of the knee-joint (Tab. 3). In theexperiments in which the abovementioned compound 13 was applied, thesubstance was added (about 30 μΙ of a 10 μΜ solution) to the spinalmedulla about 30 minutes before inducing the inflammation. The responsesof the cell to non-noxious and noxious stimulation were then subsequentlymonitored as in the control experiments. 012907 40

Comparison of the changes in the responses in the two groupe shows that,as compared with the Controls, compound 13 almost completelysuppressed the development of spinal hyperexcitability (Tab. 3). Takenoverall, the effect of compound 13 on the responses to noxious knee-joint 5 stimulation was more strongly expressed than was the effect ofindomethacin, as was shown by a comparison with published data from anearlier study.

Table 3: Neuronal responses before and during knee-joint inflammation 10 (imp/15s)

Noxious stimulation at the knee-joint

Time (min) after K/C Mean value SEM Mean value SEM injection Compound 13 compound 13 control control Baseline 0.8 29.9 0 0 30-60 62.3 49.3 161.6 43.7 60-120 26.9 35 458.1 125.4 120-180 8.5 58.9 544.2 140.0 180-240 19.5 59.9 616.3 174.7

Non-noxious stimulation at the knee-joint

Time (min) after K/C Mean value SEM Mean value SEM injection Compound 13 compound 13 control control Baseline 0.92 16.90 0 0 30-60 8.66 23.76 21.4 11.9 60-120 2.71 25.94 74.6 38.3 120-180 11.16 24.22 105.7 39.0 180-240 39.78 25.09 149.7 44.3 The effect of N-((S)-1 -carbamoyl-2-diphenyIaminoethyl)-2-(2- 15 methylaminopyrimidin^-ylJ-IH-benzimidazole-S-carboxamide, termedcompound 22 below, was also tested in model 2. 012907 41

Control data: see Table 3

Table 4: Neuronal responses before and during knee-joint inflammation (imp/15s) Noxious stimulation at the knee-joint Time (min) Compound 22 Compound 22 after K/C Experiment 1 Experiment 2 injection Baseline 0 0 30-60 -109.1 -9.2 60-120 -101.1 120-180 -37.8 60 180-240 96.7

Non-noxious stimulation at the knee-joint Time (min) Compound 22 Compound 22 after K/C Experiment 1 Experiment 2 injection 0 Baseline 0 0 30-60 -34.1 -30.6 60-120 -37.2 120-180 -32.1 50.3 180-240 68.7

The data verify the good effect of compound 22 in model 2. 012907 42 3rd model: Zymosan-induced paw inflammation in the mouse;

Parameter: paw withdrawal time during thermal stimulation of the hind paw.

Experimental implémentation: In short-term anesthésia using isoflurane,25 μΙ of a suspension containing 50 mg of zymosan/ml were injected intothe right hind paw of the experimental animal. The development of ahyperalgesia was then determined quantitatively as follows:

Determining the paw withdrawal time during thermal stimulation(Hargreave’s test; see above).

The experimental animal was placed in a transparent plastic chamberhaving a glass floor. As soon as the experimental animal was no longermoving, following the reconnaissance phase (about 5 min), an infrared lightsource was positioned directly below the hind paw to be stimulated andswitched on. The lamp emitted focused infrared light of increasing intensitysuch that the skin température of the hind paw increased almost linearly.As soon as the animal withdrew the paw, the lamp switched itself off. Thetempérature of the paw at the time it is withdrawn has just becomeunpleasant for the animal; this is referred to as the thermal pain threshold.

Shortly before the zymosan injection, and for from 7 to 14 days after theinjection, the thermal pain threshold was determined once daily on the righthind paw and left hind paw. Subsequently, the intégral of the area whichwas formed from the curves for the paw withdrawal times of the inflamedpaw and the noninflamed paw (AUC, area between the curves, seetables 5 and 6) was determined as a measure of the hyperalgesia. Thelarger this value is, the more pronounced is the hyperalgesia, and thesmaller the value is in animais which are being given the substance, thegreater is the success of the therapy.

In a 7-day study, the zymosan injection induced pronounced thermalhyperalgesia in a control group (see vehicle, tab. 5). In the other groups,the substance was administered for the first time one day after thezymosan injection, after marked thermal hyperalgesia had alreadydeveloped. Compound 13 was then administered orally twice daily for 7days, in each case at the rate of 25 or 75 mg/kg in HEC/lipofundin (1%HEC in lipofundin). Analysis of the paw withdrawal times during the entireperiod of the study (7 days) showed that, when the substance was 012907 43 administered, the AUC decreased in a dose-dependent manner. At singledoses of from 8.3 mg/kg and upwards, a significant therapeutic effect wasachieved as compared with the vehicle group (tab. 5). Compound 13exhibits very strong activity in the test model. A very high dose of 5 paracétamol was likewise administered twice daily to another group ofanimais which was taken through the experiment in parallel. Compound 13reduced the thermal hyperalgesia to a greater extent than did paracétamol(tab. 5). 10 Table 5 Thermal hyperalgesia during the seven days following zymosaninjection AUC mean value [measure ofhyperalgesia] Standard error of the arithmetic mean (SEM) Number of animais per group Statistical différence as compared with the vehicle Vehicle 45.1 1.5 8 Paracétamol, 200 mg/kg 24.6 4.1 8 yes Compound 13, 2.8 mg/kg 40.4 2.4 8 no Compound 13, 8.3 mg/kg 32.3 2.2 8 yes Compound 13, 25 mg/kg 19.4 2.9 8 yes Compound 13, 75 mg/kg 17.4 2.6 8 yes

In another study carried out on mice, the activity of compound 13 wascompared with that of the spécifie COX-2 inhibitor Celecoxib. The scheme 15 for zymosan injection and dosing was identical to that in the previouslydescribed study. The only différence was that this additional study ran for14 days.

Once again, compound 13 was able to reduce thermal hyperalgesia in adose-dependent manner (tab. 6). In the experiment, compound 13 and 20 Celecoxib had equally strong effects at the high dosage (tab. 6). 012907 44

Table 6 Thermal hyperalgesia during the 14 days following zymosaninjection AUC mean value [measure ofhyperalgesia] Standard error of the arithmetic mean (SEM) Number of animais per group Statistical différence as compared with the vehicle Vehicle 90.0 5.1 8 Celecoxib, 8.3 mg/kg 79.9 5.9 5 no Celecoxib, 25 mg/kg 51.5 3.7 9 no Compound 13, 8.3 mg/kg 64.5 5.0 5 yes Compound 13, 25 mg/kg 47.6 4.4 9 yes 4th model: Zymosan-induced paw inflammation in the mouse;

Parameter: spontaneous running performance in a running wheel.

In the cage in which it is kept, the experimental animal has access to arunning wheel, the révolutions of which are recorded electronically. Duringthe night hours, the C57/B6 mice use the running wheel voluntarily and,after a one-week phase of acclimatization, cover on average4 100 meters/night. After zymosan has been injected, the distance runeach night is reduced. This réduction in running performance is a validparameter for a restriction in function which is due to inflammation pain.Experimental implémentation: After an acclimatization phase of oneweek, the distance run/24 hours was measured in order to détermine thebase line. 25 pl of a suspension containing 50 mg of zymosan/ml were theninjected into the right hind paw of the experimental animal during short-termanesthésia using isoflurane. The distance run/24 hours was thendetermined during the following seven days. In the analysis, the area underthe curve for the values for the distance run was determined (AUC, tab. 7):the lower the AUC, the lower was the running performance during the weekfollowing injection of the zymosan. Compound 13 was administered twicedaily for 7 days, with the dose in each case being 25 or 75 mg/kg inHEC/lipofundin (1% HEC in lipofundin). The substance was administeredfor the flrst time on day 1 after injection of the zymosan.

In one study, the effect of compound 13 on running performance followingzymosan injection was compared with that of paracétamol. A dose-dependent increase in the distance run, which was significant as comparedwith the vehicle group, was found in the case of both the higher doses(tab. 7). By contrast, no improvement as compared with the vehicle group 012907 45 was achieved when paracétamol was used at an extremely high dose (also2 x daily) (tab. 7).

Table 7 Running wheel activity during the seven days following zymosan5 injection _ AUC mean value Standard error of the arithmetic mean (SEM) Number of animais per group Statistical différence as compared with the vehicle Vehicle 108.8 12.5 8 Paracétamol, 200 mg/kg 187.2 42.7 8 no Compound 13, 2.8 mg/kg 131.1 23.3 8 no Compound 13, 8.3 mg/kg 142.1 29.1 8 no Compound 13, 25 mg/kg 216.7 58.5 8 yes Compound 13, 75 mg/kg 251.7 41.9 8 yes

Claims (10)

1. The use of the compound of the formula l 46 012907 Patent daims:

   and/or a stereoisomeric form of the compound of the formula land/or a physiologically tolerated sait of the compound of theformula I, for producing pharmaceuticals for treating pains, where E is N atom or the radical -C(R19)-, where R19 is hydrogen atom or the radical Rs, one of the substituents R1, R2, R3 and R4 is a radical of the formula II,

   R' in which D is -C(O)-, -S(O)- or -S(O)2-, R8 is hydrogen atom or -(Ci-C4)-alkyl, R9 is 1. characteristic radical of an amino acid, 2. aryl, in which aryl is unsubstituted or substituted, 3_ heteroaryl having from 5 to 14 ring members, in whichheteroaryl is unsubstituted or substituted, 4. heterocycle having from 5 to 12 ring members, inwhich heterocycle is unsubstituted or substituted, or 5. (CrCgl-alkyl, in which alkyl is straight-chain orbranched and is unsubstituted or is substituted, once,twice or three times, independently of each other, by5.1 aryl, in which aryl is unsubstituted or substituted, 5.2 heteroaryl having from 5 to 14 ring members, inwhich heteroaryl is unsubstituted or substituted, 47 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15 012907 heterocycle having from 5 to 12 ring members,in which heterocycle is unsubstituted orsubstituted, -O-R11, =O, halogen, -CN, -CF3, -S(O)X-R11, in which x is the integer zéro, 1 or 2,-C(O)-O-R11, -C(O)-N(R11)2, -C(O)-R11, -N(R11)2, -(C3-C6)-cycloalkyl, radical of the formula R11

   or 5.16 radical of the formula - R11 in which R11 is a) hydrogen atom, b) -(CvCeJ-alkyl, in which alkyl is unsubstituted or is substituted once, twice or three times, 1. aryl, in which aryl is unsubstituted orsubstituted, 2. heteroaryl having from 5 to 14 ring members, 3. heterocycle having from 5 to 12 ring members, 4. halogen, 5. -N-(C1-C6)n-alkyl, in which n is the integer zéro, 1 or 2 and alkyl is unsubstituted oris substituted once, twice or three times, 012907 48 independently of each other, by halogenor by -C(O)-OH, 6. -O-(CrC6)-alkyl or 7. -C(O)-OH, c) aryl, in which aryl is unsubstituted orsubstituted, d) heteroaryl having from 5 to 14 ring members, or e) heterocycle having from 5 to 12 ring members,and, in the case of (R11)2, R11 has, independently of each other, themeanings of a) to d), Z is 1. aryl, in which aryl is unsubstituted or substituted, 2. heteroaryl having from 5 to 14 ring members, in whichheteroaryl is unsubstituted or substituted, 3. heterocycle having from 5 to 12 ring members, inwhich heterocycle is unsubstituted or substituted, 4. -(Ci-C6)-alkyl, in which alkyl is substituted or unsubstituted, 5. -C(O)-R11, 6. -C(O)-O-R11 or 7. -C(O)-N(R11)2, or R8 and R9 form, together with the nitrogen atom and carbon atom towhich they are bonded, a heterocyclic ring of the formula lia, (Ua)

   in which D and Z are defined as in formula II, A is nitrogen atom or the radical -CH2-, B is oxygen atom, sulfur atom, nitrogen atom or the radical -CH2-, X is oxygen atom, sulfur atom, nitrogen or the radical -CH2-, Y is absent or is oxygen atom, sulfur atom, nitrogenatom or the radical -CH2-, or 012907 49 X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or 1,4-diazine radical, where the ring System which is formed by N, A, X, Y, B and carbonatom does not contain more than one oxygen atom, X is not oxygenatom, sulfur atom or nitrogen atom when A is nitrogen atom, doesnot contain more than one sulfur atom, and contains 1, 2, 3 or 4nitrogen atoms, and where an oxygen atom and a sulfur atom arenot présent simultaneously, where the ring System which is formed by N, A, X, Y, B and carbonatom is unsubstituted or is substituted, once, twice or three times,independently of each other, by -(CX-CsJ-alkyl, in which alkyf isunsubstituted or is substituted, once or two times, by 1.1. -OH, 1.2. -(Ci-C8)-alkoxy, 1.3. halogen, 1.4. -NO2, 1.5. -NH2, 1-6. -CF3, 1.7. methylenedioxyl, 1.8. -C(O), 1.9. -C(O)-CH3, 1.10. -(Ci-C4)-alkoxycarbonyl, 1.11. -CN, 1.12. -C(O)-OH, 1.13. -C(O)-NH2, 1.14. tetrazolyl, 1.15. phenyl, 1.16. phenoxy, 1.17. benzyl or 1.18. benzyloxy or R9 and Z form, together with the carbon atoms to which they are ineach case bonded, a heterocyclic ring of the formula Ile, D

   R11 (Hc) 50 012907 in which D, R8 and R11 are defined as in formula II, T is oxygen atom, sulfur atom, nitrogen atom or the radical -CH2-, W is oxygen atom, sulfur atom, nitrogen atom or the radical -CH2-, Vis absent or is oxygen atom, sulfur atom, nitrogenatom or the radical -CH2-, or T and V or V and W together form a phenyl, 1,2-diazine,1,3-diazine or 1,4-diazine radical, where the ring System which is formed by N, T, V, W andtwo carbon atoms does not contain more than one oxygenatom, does not contain more than one sulfur atom andcontains 1, 2, 3 or 4 nitrogen atoms, where an oxygenatom and a sulfur atom are not présent simultaneously,and where the ring System which is formed by N, T, V, Wand two carbon atoms is unsubstituted or is substituted,once to three times, independently of each other, by thesubstituents which are defined above under 1.1. to 1.18.,and the other substituents R1, R2, R3 and R4 in each case are,independently of each other, 1. hydrogen atom, 2. halogen, 3. -(CrC6)-alkyl, 4. heteroaryl having from 5 to 14 ring members, in whichheteroaryl is unsubstituted or substituted, 5. heterocycle having from 5 to 12 ring members, inwhich heterocycle is unsubstituted or substituted,
2. 2. -OH, or 3. =0, and R6 is 1. phenyl, substituted, once ortwice, by 1.1 -CN, 1.2 -NO2, 1.3 -O-(CrC4)-alkyi, or 1.4 -NH2, or 2. is pyridine or pyrimidine, where pyridine or pyrimidine is unsubstituted or substituted,once, twice or three times, by identical or different radicaisfrom the sériés -C(O)-(Ci-C4)-alkyl, -C(O), =0, -NH-(C1-C4)-aikyl, -NH-((C1-C4)-alkyl)2, -(CvC^-alkyl, -(C^Cabalkoxy,halogen, nitro, amino, trifluoromethyt, hydroxyl, -CF3,hydroxy-(C-i-C4)-alkyl such as hydroxymethyl or1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyl, -(Ci-C4)-alkoxycarbonyl, pheny!, phenoxy,benzyl, benzyloxy, -S(O)X-R11, in which x is the integer zéro, 1or 2, -O-fCvC^-alkyl, -C(O)-OH, -C(O)-O-(CrC4)-aikyl,-NH-C(O)-(Ci-C4)-alkyl or tetrazolyl.

   2. -OH, or 3. =0, and R6 is 1. aryl, from the group naphthyi, 1-naphthyl, 2-naphthyi, phenyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl orfluorenyl, in which aryl is unsubstituted or substituted, once, twice or threetimes, by identical or different radicals from the sériés -C(O)-(Ci-C4)-alkyl, -C(O), =0, -NH-(Ci-C4)-alkyl, -NH-((Ci-C4)-alkyl)2, -(CtCs)-alkyl, -(CT-Cg^alkoxy, halogen, nitro, amino, trifluoromethyl,hydroxyl, -CF3, hydroxy-(Ci-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethyienedioxy,formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(CrC4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)X-R11, inwhich x is the integer zéro, 1 or 2, -O-(Ci-C4)-alkyl, -C(O)-OH,-C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(CrC4)-alkyl or tetrazolyl, or 2. heteroaryl having from 5 to 14 ring members, in whichheteroaryl is defined as above and in which heteroaryl is unsubstituted or substituted, once, twice orthree times, by identical or different radicals from the sériés -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(Ci-C4)-alkyl, -NH-((C1-C4)-alkyl)2l 012907 56 -(Ci-C8)-alkyl, -(Ci-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl,hydroxyl, -CF3, hydroxy-(Ci-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy,formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)X-R11, inwhich x is the integer zéro, 1 or 2,-O-(C1-C4)-aikyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(CrC4)-alky! ortetrazolyl.
3. The use of the compound of the formula I as claimed in claim 1,wherein Ξ is N atom or the radical -C(R19)-, in which R19 is hydrogen atom, one of the substituents R1, R2, R3 and R4 is a radical of the formulaII, in which R8 is hydrogen atom, R9 is 1. a characteristic radical of an amino acid from the grouphistidine, serine, tryptophan, threonine, cysteine, méthionine,asparagine, glutamine, lysine, arginine, glutamic acid andaspartic acid, or 2. -(Ci-C6)-alkyl, in which alkyl is straight-chain orbranched and is unsubstituted or substituted, once or twice,by a) phenyl, b) a radical from the group azepine, azetidine, benzimidazole, benzothiazole, benzothiophene, benzoxazole,diazepine, imidazole, indole, isothiazole, isoxazole,morpholine, 1,3,4-oxadiazole, 5-oxo-4,5-dihydro- [1,3,4]oxadiazole, oxazole piperidine, pyrazine, pyrazole,pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, thiazole,thiomorpholine, thiophene ortriazole, c) -NH(R11), d) -C(O)-R12, in which R12 is naphthyl, phenyl, morpholinyl or pyrimidinyl, e) -O-R11, f) -N(R12)-phenyl, in which R12 is defined as above, g) -S(O)X-R12, in which x is zéro, 1 or 2, and h) -CN, or 012907 57 i) -(C3-C6)-cycloalkyl, and the radicale defined above by a), b), d) and i) and R12 are unsubstituted or are substituted, once or twice, by -OH, -(C-i-C^^alkyl, -CF3, halogen, -O-(C-,-C4)-alkyl, -COOH, -C(O)-O-(Ci-C4)-alkyl, -NH2 or -NH-C(O)-(C1-C4)-alkyl, Z is 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline, indazole,isothiazole, isothiazolidine, isoxazole, isoxazolidine, 2-isoxazolidine, isoxazolone, morpholine, 1,3,4-oxadiazole,oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide, oxazole, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazolidine,pyrazoline, pyridazine, pyrimidine, tetrazole, thiadiazole,thiazole, thiomorpholine, triazole or triazolone, andthe heteroaryl radical is unsubstituted or substituted, once,twice or three times, independently of each other, by 1.1 -C(O)-R15, in which R15 is hydrogen atom or -(Ci-C4)-alkyl, 1.2 -(CrCzû-alkyl, 1.3 -O-R15, in which R15 is hydrogen atom or -(C-i-C4)-aIkyl, 1.4 -N(R15)-R16, in which R15 and R16 are, independently ofeach other, hydrogen atom or -(Ci-C4)-alkyl, 1.5 halogen, or 1.6 keto radical, 2. -C(O)-R15, in which R15 is hydrogen atom or -(C-i-C4)-alkyl, 3. -C(O)-R15, in which R15 is hydrogen atom or -(Ci-C4)-alkyl, or 4. -C(O)-N(R15)R15, in which R15 and R16 are,independently of each other, hydrogen atom or-(C-|-C4)-alkyl, R11 is 1. -(CrC4)-alkyl, 2. R13 or, 3- -N(R13)2, in which R13 is, independently of each other, a) hydrogen atom, b) -(Ci-C6)-alkyl, c) -(C1-C4)-alkyl-O-(Cl-C4)-alkyl, 012907 58 d) -(Ci-C6)-alkyl-N(R15)2, in which R15 is defined asabove, or e) -(C0-C4)-alkyl which is substituted, once or twice, byimidazolyl, morphoiinyl or phenyl, or R8 and R9 form, together with the nitrogen atom and carbon atom towhich they are in each case bonded, a ring of the formula lia fromthe group pyrrole, pyrroline, pyrrolidine, pyridine, piperidine,piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole,imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine,oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine,isothiazole, thiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides,oxadiazolone, isoxazolone, triazolones, oxadiazolidinedione,triazole, which are substituted by F, CN, CF3 or COO-(Ci-C4)-alkyl,3-hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles, 1,3,4-oxadiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole,benzimidazole, quinoline, triazole, phthalazine, quinazoline,quinoxaline, purine, pteridine, indole, tetrahydroquinoline,tetrahydroisoquinoline and isoquinoline, or R9 and Z form, together with the carbon atoms to which they are ineach case bonded, a ring of the formula Ile from the group pyrrole,pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine,pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline,imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2- isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole,quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine,pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline,isoquinoline, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, oxadiazolone, isoxazolone, triazolones, oxadiazolidinedione,triazole, which are substituted by F, CN, CF3 or COO-(Ci-C4)-alkyl, 3- hydroxypyrro-2,4-diones, 1,3,4-oxadiazole and 5-oxo-1,2,4-thiadiazole and the other substituents R1, R2, R3 and R4 in each case are,independently of each other, 1. hydrogen atom, 2. halogen, 3. -(CrC4)-alkyl,

   2. The use of the compound of formula I as claimed in claim 1, wherein E is N atom or the radical -C(R19)-, in which R19 is hydrogen atom or the radical R9, one of the substituents R1, R2, R3 and R4 is a radical of the formula II, in which D is -C(O)-, -S(O)- or -S(O)2-, R8 is hydrogen atom or (C1-C4)-alkyl, R9 is 1. a characteristic radical of an amino acid which isderived from a naturally occurring α-amino acids of the groupalanine, valine, leucïne, isoleucine, phenylalanine, tyrosine,tryptophan, serine, threonine, cysteine, méthionine,asparagine, glutamine, lysine, histidine, arginine, glutamicacid and aspartic acid, 2. a characteristic radical of an amino acid which isderived from an amino acid which is not naturally occurring,such as 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid, 1,2,3,4,-tetrahydroisoquinoline-1- 012907 52 carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid, 2-aiminopimelic acid, 3-(2-thienyl)aianine, 3-(3-thienyl)alanine, sarcosine, pipecolic acid, 2-aminoheptanoicacid, hydroxylysine, N-methylisoleucine, 6-N-methyllysine,norleucine, N-methylvaline, non/aline, omithine, allo-isoleucine, 4-hydroxyproline, allo-hydroxyîysine, allo-threonine, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homocystéine, homophenylalanine,homocysteic acid, 2-amino-3-phenylaminoethylpropionic acid, 2- amino-3-phenylaminopropionic acid, homotryptophan,cysteic acid, 3-(2-pyridyl)aianine, 3-(3-pyridyl)alanine, 3-(4-pyridy!)alanine, phosphinothricin, 4-fluorophenytaianine, 3- fluorophenylalanine, 2-fluorophenyialanine, 4- chlorophenylalanine, 4-nitrophenylalanine, cyclohexylalanine, 4- aminophenylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, méthionine sulfone, méthionine sulfoxideor -NH-NR11-CON(R11)2, in which R11 is defined as below, 3. aryl, from the group anthryl, biphenyiyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, fluorenyl, naphthyl, 1-naphthyl,2-naphthyl or phenyl, in which aryl is unsubstituted orsubstituted once, twice or three times by identical or differentradicals from the sériés -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-alkyl)2, -(CrC8)-alkyl, -(CrC8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3,hydroxy-(C1-C4)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyl, -(Ci-C4)-alkoxycarbonyl, phenyl, phenoxy,benzyl, benzyloxy, -S(O)X-R11 in which x is the integer zéro, 1or 2, -O-(C-i-C4)-alkyl, -C(O)-OH, -C^-CHCrC^-alkyl,-NH-C(O)-(Ci-C4)-alkyl or tetrazolyl, 4. heteroaryl having from 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted and, as a radical, isderived from the group azepine, azetidine, benzimidazole,benzodioxolane, 2-benzofuran, benzothiazole, benzothiophene, 2-benzothiophene, 2-benzoxazole, β-carboline, quinoxaline, quinazoline, quinoline, 2-quinoxaline,cyclohepta[b]-5-pyrrole, diazepine, dihydropyridine, 3- 012907 53 hydroxypyrro-2,4-dione, imidazole, 4-imidazole, imidazolidine,imidazoline, indazole, indole, isoquinoline, isoindole,isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine,isoxazolidine, isoxazolone, methylimidazole, 3-(N-methylpyrrolidine), morpholine, oxazole, 1,3,4-oxadiazole,oxadiazolidinedione, oxadiazolone, 5-oxo-4,5-dihydro- [1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole, 1,2,3,5-oxathiadiazole-2-oxide, 1 -oxo-1,2-dihydro-3-isoquinol, phenylpyrrole, 5-phenyl-2-pyrrole, phthalazine, piperazine,piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine,pyrazoline, pyridazine, pyrimidine, pyridine, pyridyl-N-oxide,2-pyrrole, 3-pyrrole, pyrrolidine, pyrroline, 4,5,6,7-tetrahydro-2-indole, tetrahydrothienyl, tetrazole, thiadiazole, thiazole,thiomorpholine, thiophene, triazole, triazolone or triazole, in which heteroaryl is unsubstituted or substitutedonce, twice or three limes by identical or different radicalswhich are derived from the sériés -C(O)-(Ci-C4)-alkyl, -C(O),=0, -NH-tCrC^-alkyl, -NH-((Ci-C4)-alkyl)2, -(C^C^-alkyl,-(Ci-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl,hydroxyl, -CF3, hydroxy-(C-i-C4)-alkyl such as hydroxymethylor 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyl, -(C-i-C4)-alkoxycarbonyl, phenyl, phenoxy,benzyl, benzyloxy, -S(O)X-R11, in which x is the integer zéro, 1or 2, -O-(CrC4)-alkyl, -C(O)-OH, -qOKHCrC^-alkyl,-NH-C(O)-(Ci-C4)-alkyl or tetrazolyl, 5. -(Ci-C6)-alkyl in which alkyl is straight-chain orbranched and is unsubstituted or substituted once, twice orthree times, independently of each other, by 5.1 aryl, in which aryl is defined as above, 5.2 heteroaryl having from 5 to 14 ring members, in whichheteroaryl is defined as above, 5.3 -(C3-C6)-cycloalkyl, 5.4 -O-R11, 5.5 =0, 5.6 halogen, 5.7 -CN, 5.8 -CF3, 012907 54 5.9 5.10 S(O)XR11, in which x is the integer zéro, 1 or 2,C(O)-O-R11, 5.11 -C(O)-N(R11}2, 5.12 -C(O)-R11, 5.13 -N(R11)2, 5.14 a radical of the formula R11

   or 5.15 a radical of the formulain which R11 is a) hydrogen atom, R11 b) c) d) (C-i-C6)-alkyl in which alkyl is unsubstituted orsubstituted once, twice orthree times by aryl, in which aryl is defined as above,heteroaryl having 5 to 14 ring members,in which heteroaryl is defined as above,halogen, -N-(Ci-C6)n-alkyl, in which n is the integerzéro, 1 or 2 and alkyl is unsubstituted orsubstituted once, twice or three times,independently of each other, by halogen or by -C(O)-OH, 5. -O-(Ci-C6)-alkyl or 6. -C(O)-OH, aryl, in which aryl is defined as above, orheteroaryl having from 5 to 14 ring members, inwhich heteroaryl is defined as above, and in the case of (R )2, the radical R has, independently ofeach another, the meaning of a) to d), Z is 1. aryl in which aryl is defined as above, 2. heteroaryl having from 5 to 14 ring members, in whichheteroaryl is defined as above, 3. -(CrCe^alkyl, in which alkyl is straight-chain orbranched and is substituted once or twice by phenyl or -OH, 4. -C(O)-O-R11, or 55 0 4 r, A Λ i ζ y u / 5. -C(0)-N(R11)2, and the other substituents R1, R2, R3 and R4 are in each case,independently of each other, 1. hydrogen atom, 2. halogen, 3. -(C1-C4)-alkyl, 4. heteroaryl having from 5 to 14 ring members, in whichheteroaryl is defined as above, 5. -(CrCsJ-alkyl,

   2. -OH or 3. =0, and R6 is 1. aryl, in which aryl is unsubstituted orsubstituted, 2. phenyl which is substituted once or twice by 2.1 -CN, 2.2 -NO2, 2.3 -0-(^-C4)-alkyl, 2.4 -N(R11)2, 2.5 -NH-C(O)-R11, 2.6 -S(O)s-R11, in which s is the integer zéro, 1 or 2, 2.7 -C(O)-R11 or 2.8 -(C1-C4)-alkyl-NH2, 3. heteroaryl having from 5 to 14 ring members, isunsubstituted or is substituted once, twice or threetimes, or 4. heterocycle having from 5 to 12 ring members,is unsubstituted or is substituted once, twice orthree times.
4. 4. -CN, 5- -CF3,

   4. The use of the compound of formula I as claimed in claim 1, whereinE is the radical -C(R19)-,in which R19 is hydrogen atom or R9, one of the substituents R1, R2, R3 and R4 is a radical of the formula IIin whichD is -C(O)-, R8 is hydrogen atom, Z is 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, -C(O)-OH or -C(O)-NH2,

   η 60 R9 is 1. -(Ci-C4)-alkyl, in which alkyl is straight-chain orbranched and is substituted once or twice, independentiy ofeach other, by 1.1 -S(O)-R11, where R11 is defined as below, 1.2 -N(R11)2, where R11 is defined as below, or 1.3 pyrrole, or 2. the characteri'stic radical of an amino acid from thegroup histidine, tryptophan, serine, threonine, cysteine,méthionine, asparagine, glutamine, lysine, arginine,glutamic acid and aspartic acid, R11 is a) hydrogen atom, b) -(Ci-C6)-alkyl, in which alkyl is unsubstituted orsubstituted, once to three times, independentiy of eachother, by halogen, or c) phenyl, in which phenyl is unsubstituted or substituted,once to three times, independentiy of each other, byhalogen or -(C1-C4)-alkyl, the other substituents R1, R2, R3 and R4 are in each case hydrogenatom, R5 is hydrogen atom, and R6 is phenyl, pyridine or pyrimidine, where phenyl, pyridine or pyrimidine is unsubstituted or substituted,once, twice or three times, by identical or different radicalsfrom the sériés -C(O)-(CrC4)-alkyl, -C(O), =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-alkyl)2, -(CrCal-alkyl, -(Ci-C8)-alkoxy,halogen, nitro, · amino, trifluoromethyl, hydroxyl, -CF3,hydroxy-(C-i-C4)-alkyl such as hydroxymethyl or1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyl, -(Ci-C4)-alkoxycarbonyl, phenyl, phenoxy,benzyl, benzyloxy, -S(O)X-R11, in which x is the integerzero, 1or 2, -O-(Ci-C4)-alkyl, -C(O)-OH, -C^-CHCrC^-alkyl,-NH-C(O)-(Ci-C4)-alkyl or tetrazolyl. 5. The use of the compound of the formula la as claimed in claim 1 01

   and/or a stereoisomeric form of the compound of the formula laand/or a physiologically tolerated sait of the compound of theformula la, where E and M are identical or different and are, independently of eachother, N atom or CH, R21 and R31 are identical or different and are, independently ofeach other, 1. hydrogen atom, 2. halogen, 3. -(Ci-C4)-alkyl,

   4. -CN, 59 01290 7
5. 5. -NO2, 6. -O-(Cô-C4)-alkyl-phenyl, 7. -O-(Ci-C4)-alkyl, 8. -N-(C0-C4)-alkyl-phenyl, 9. -N-(CrC4)-alkyl or

   10. -CF3, R5 is 1. hydrogen atom,
6. 6. The use of the compound of the formula la as claimed in claim 5,wherein E and M are identical or different and are, independently of eachother, N atom or CH, R21 and R31 are identical or different and are, independently ofeach other, as defined as above under 1. to 9., R22 is ΐ: a heteroary! radical from the group imidazole, isothiazole, isoxazole, 2-isoxazolidine, isoxazolidine,isoxazolone, 1,3,4-oxadiazole, oxadiazolidinedione, 1,2,3,5-oxadiazolone, oxazole, 5-oxo-4,5-dihydro[1,3,4]oxadiazole,tetrazole, thiadiazole, thiazole, triazole or triazolone, and theheteroaryl radical is unsubstituted or is substituted once,twice or three times, independently of each other, by 1.4 keto radical, 1.5 halogen or 1.6 -(CrC2)-alkyl, or 2. -C(O)-N(R17)-R18, in which R17 and R13 are, independently of each other, hydrogen atom, -(C1-C2)-alkyl-OH, -O-ÎCv^-alkyi or —(G-,-C4)-alkyl, R23 is hydrogen atom, methyl orethyl, R24 is 1. a heteroaryl radical from the group of the unsaturated,partially saturated or completely saturated rings which arederived from pyridine, pyrazine, pyrimidine, pyridazine,pyrrole, furan, thiophene, imidazole, pyrazole, oxazole,isoxazole, thiazole, triazole or isothiazole, where the heteroaryl radical is unsubstituted or is substituted,once, twice or three times, independently of each other, by-(C-!-C4)-alkyl, -(Cr^J-alkoxy, F, Cl, I, Br, nitro, amino,trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylene-dioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyl or-(Ci-C4)-alkoxycarbonyl, or 2. phenyl and phenyl is unsubstituted or is substituted once, twice or three times, independently of each other, by F, Ci, I, Br, CF3, -OH, -(C-i-C^-alkyl or-(Oi-C4)-alkoxy. 012907 64

   6. -OR15, in which R15 is hydrogen atom or-(Ci-C4)-alkyl, 7. -N(R15)-R16, in which R15 and R16 are, independently of eachother, hydrogen atom or-(Ci-C4)-alkyl, 8. -C(O)-R15, in which R15 is hydrogen atom or-^CTC^-alkyl, or 9. -S(O)X-R15, in which x is the integer zéro, 1 or 2, and R15 ishydrogen atom or -{Ci-C4)-alkyl, R22 is 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline, indazole,isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine,isoxazolidine, isoxazolone, morpholine, oxazole, 1,3,4-oxa-diazole, oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathia-diazole-2-oxide, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazoline,pyrazolidine, pyridazine, pyrimidine, tetrazole, thiadiazole,thiazole, thiomorpholine, triazole or triazolone, and 012907 62 the heteroaryl radical is unsubstituted or substituted once, twice or three times, independently of each other, by 1.1 -C(O)-R15, in which R15 is hydrogen atom or -(Ci-C4)- alkyl, 1.2 -(CrC4)-alkyl, 1.3 -O-R15, in which R15 is hydrogen atom or -(CrC4)- alkyi, 1.4 -N(R15)-R16, in which R15 and R16 are, independently ofeach other, hydrogen atom or -(C-i-C4)-alkyl, 1.5 halogen, or 1.6 keto radical, 2. -C(O)-R15, in which R15 is hydrogen atom or -(Ci-C4)-alkyl, 3. -C(O)-OR15, in which R15 is hydrogen atom or -(CVC4)-alkyl, or 4. -C(O)-N(R17)-R18, in which R17 and R18 are,independently of each other, hydrogen atom, -(Ci-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(Ci-C4)-alkyl, R23 is hydrogen atom or-(Ci-C4)-alkyl, R24is1. a heteroaryl radical from the group pyrrole, furan,thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxide,triazolones, oxadiazolones, isoxazolones, oxadiazolidine-dione, triazole, 3-hydroxypyrro-2,4-dione, 5-oxo-1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, indole, isoindole,indazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline, β-carboline and benzo fusedcyclopenta dérivatives or cyclohexa dérivatives of theseheteroaryl radicals, where the heteroaryl radical is unsubstituted or substituted,once, twice or three times, independently of each other, by-(Ci-C5)-a!kyl, -(Ci-Cs)-alkoxy, halogen, nitro, amino,trifluoromethyl, hydroxyl, hydroxy-(C-i-C4)-alkyl, methylene-dioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyl or-(Ci-C4)-alkoxycarbonyl, or 2. an aryl radical from the group phenyl, naphthyl,1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyland 4-biphenylyl, anthryl or fluorenyl, and 012907 63 the aryl radical is unsubstituted or is substituted, once, twice or three times, independently of each other, by -(C1-C5)-alkyl, -(Ci-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyi or -(C1.C4)-alkoxycarbonyl.

   6. -NO2,

   6. -NO2,
7. 7. The use of the compound of the formula I or la as claimed in claim 1or 5, wherein the compound N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2-yi)ethyl]-2-(2-methylaminopyrimidin-4-yl)- 1 H-indole-5-carboxamide or N-((S)-1-carbamoyl-2-diphenylamino-ethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamide is employed.

   7. -CN, 8. -O-(C0-C4)-alkyl-aryl, in which aryt is defined as above, 9. -O-(C1-C4)-alkyl,

   10. -OR11, 11. -N(R11)2, 12. -S(O)X-R11, in which x is the integer zéro, 1 or 2, or

   13. -CF3, R5 is 1. hydrogen atom,

   7. -CN, 8. -0-(Co-C4)-alkylaryl, 9. -O-ÎCrC^-alkyl,

   10. -OR11, 11. -N(R11)2, 12. -S(O)r-R11, in which r is the integer zéro, 1 or 2, or

   13. -CF3, R5 is 1. hydrogen atom, 51
8. 8. The use of the compound of the formula i or la as claimed in one ormore of daims 1 to 7 for producing pharmaceuticals for theprophylaxis and therapy of acute pains or chronic pains.
9. 9. The use as claimed in claim 8, wherein the chronic pains are chronicpains from the group chronic musculoskeletal diseases, such asback pains, pains associated with menstruation, pains associatedwith osteoarthritis or rheumatoid arthritis, pains associated withintestinal inflammation, pains associated with cardiac muscleinflammation, pains associated with multiple sclerosis, painsassociated with neuritis, pains associated with carcinomas andsarcomas, pains associated with AIDS, pains associated withchemotherapy, amputation pain, trigeminus neuralgia, headaches,for example migraine cephalalgia, or neuropathie pains, such aspost-herpes zoster neuralgia.
10. 10. The use as claimed in claim 8, wherein the acute pains are acutepains from the group pains following injuries, post-operative pains,pains associated with an acute attack of goût, or acute painsfollowing jaw-bone surgical interventions.