Patent ID: 6358978
Filing Date: 2002-03-19
Classification: A61P,C07D

Abstract:
A compound of formula I or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where one of the substituents R1, R2, R3, and R4 is a radical of formula II in which:D is â€”C(O)â€”, â€”S(O)â€”, or â€”S(O )2â€”; R8 is hydrogen or (C1-C4)-alkyl; R9 is (1) alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, or aspartic acid; (2) 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-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or â€”NHâ€”NR11â€”CON(R11)2, wherein R11 is as defined below: (3) aryl, in which aryl is unsubstituted or substituted, selected from naphthyl, biphenylyl, anthryl, and fluorenyl; (4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted, selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4-oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COOâ€”(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls; (5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by (5)(1) aryl, in which aryl is unsubstituted or substituted; (5)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted; (5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted; (5)(4) â€”Oâ€”R11; (5)(5) &boxH;O; (5)(6) halogen; (5)(7) â€”CN; (5)(8) â€”CF3; (5)(9) â€”S(O)xâ€”R11, in which x is the integer 0, 1, or 2; (5)(10) â€”C(O)â€”Oâ€”R11; (5)(11) â€”C(O)â€”N(R11)2; (5)(12) â€”N(R11)2; (5)(13) (C3-C6)-cycloalkyl; (5)(14) a radical of formula â€ƒor (5)(15) a radical of formula â€ƒin which R11 is (a) hydrogen; (b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by â€ƒ(1) aryl, in which aryl is unsubstituted or substituted; â€ƒ(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted: â€ƒ(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted; â€ƒ(4) halogen; â€ƒ(5) â€”Nâ€”(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by â€”COOH; â€ƒ(6) â€”Oâ€”(C1-C6)-alkyl; or â€ƒ(7) â€”COOH; (c) aryl, in which aryl is unsubstituted or substituted; (d) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted; or (e) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted; and â€ƒin the case of (R11)2, R11 independently of one another has the meaning of (a) to (e); Z is (1) aryl, in which aryl is unsubstituted or substituted; (2) heteroarl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted; (3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted; (4) â€”(C1-C6)-alkyl, in which alkyl is mono- or disubstituted independently of one another by (4)(1) aryl, in which aryl is unsubstituted or substituted; (4)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted; (4)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted; (4)(4) halogen; (4)(5) â€”Nâ€”(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono- , di-, or trisubstituted independently of one another by halogen or by â€”COOH; (4)(6) â€”Oâ€”(C1-C6)-alkyl; or (4)(7) â€”COOH; or (5) â€”C(O)â€”R10, in which â€ƒR10 is (1) â€”Oâ€”R11; or (2) â€”N(R11)2; in which R11 is as defined above; or R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa â€ƒin which: D, Z, and R10 are as defined in formula II; A is nitrogen or â€”CH2â€”; B is oxygen, sulfur, nitrogen, or â€”CH2; X is oxygen, sulfur, nitrogen, or â€”CH2; Y is absent or is oxygen, sulfur, nitrogen, or â€”CH2â€”; or X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical; where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom; contains no more than one sulfur; contains 1, 2, 3, or 4 nitrogens; and where oxygen and sulfur do not occur at the same time; where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or mono- or disubstituted by (1)(1) â€”OH; (1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched; (1)(3) halogen; (1)(4) â€”NO2; (1)(5) â€”NH2; (1)(6) â€”CF3; (1)(7) â€”OH; (1)(8) methylenedioxy; (1)(9) â€”C(O)â€”CH3; (1)(10) â€”CH(O); (1)(11) â€”CN; (1)(12) â€”COOH; (1)(13) â€”C(O)â€”NH2; (1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched; (1)(15) phenyl; (1)(16) phenoxy; (1)(17) benzyl; (1)(18) benzyloxy; or (1)(19) tetrazolyl; or R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc â€ƒin which: D, R8, and R11 are as defined in formula II; T is oxygen, sulfur, nitrogen, or â€”CH2â€”; W is oxygen, sulfur, nitrogen, or â€”CH2â€”; V is absent or is oxygen, sulfur, nitrogen, or â€”CH2â€”; or T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical; or V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical; where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens; where oxygen and sulfur do not occur at the same time; and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19); and the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are (1) hydrogen; (2) halogen; (3) (C1-C4)-alkyl; (4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstitued or substituted; (5) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted; or (6) (C1-C6)-alkyl; (7) â€”CN; (8) â€”NO2; (9) â€”Oâ€”(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched; (10) â€”Oâ€”(C1-C4)-alkyl; (11) â€”OR11; (12) â€”N(R11)2; (13) â€”S(O)xR11, in which x is the integer 0, 1, or 2; or (14) â€”CF3; â€ƒin which R11 is as defined above; R5 is (1) hydrogen; (2) â€”OH; or (3) &boxH;O; and R6 is (1) aryl, in which aryl is unsubstituted or substituted, and is selected from phenyl, naphthyl, biphenylyl, anthryl, and fluorenyl, in which aryl is unsubstituted, monosubstituted, or polysubstituted independently of one another by (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxytarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, and tetrazolyl; or (2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted and is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4 oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COOâ€”(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoitne, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls.