Use of Antagonists of the Bradykinin B2 Receptor for the Treatment of Osteoarthrosis

A method for treating a degenerative joint disease, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of formula I

• A-B-X-E-F-K-(D)-TIC-G-M-F′-I (I)
• wherein:
• A is hydrogen, (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C1-C8)-alkoxycarbonyl or (C1-C8)-alkylsulfonyl, each of which is optionally substituted one, two or three times by carboxyl, amino, (C1-C4)-alkyl, (C1-C4)-alkyl-amino, hydroxy, (C1-C3)-alkoxy, halogen, di-(C1-C4)-alkyl-amino, carbamoyl, sulfamoyl, (C1-C4)-alkoxycarbonyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C5)-alkyl, or each of which is optionally substituted one time by (C3-C8)-cycloalkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkylsulfinyl, (C6-C12)-aryl-(C1-C4)-alkylsulfonyl, (C6-C12)-aryl-(C1-C4)-alkylsulfinyl, (C6-C12)-aryloxy, (C3-C9)-heteroaryl or (C3-C9)-heteroaryloxy, and is further optionally substituted one or two times by carboxyl, amino, (C1-C4)-alkylamino, hydroxy, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C5)-alkyl, wherein the heteroaryl is optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl, (C3-C8)-cycloalkyl, carbamoyl, which is optionally substituted on the nitrogen by (C1-C6)-alkyl or (C6-C12)-aryl, (C6-C12)-aryl, (C6-C12)-aroyl, (C6-C12)-arylsulfonyl, (C3-C9)-heteroaryl or (C3-C9)heteroaroyl, wherein the heteroaryl, aroyl, arylsulfonyl and heteroaroyl are each independently optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl, or of formula II,
• wherein
• R(1) is hydrogen, (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C1-C8)-alkoxycarbonyl or (C1-C8)-alkylsulfonyl, each of which is optionally substituted one, two or three times by carboxyl, amino, (C1-C4)-alkyl, (C1-C4)-alkyl-amino, hydroxy, (C1-C3)-alkoxy, halogen, di-(C1-C4)-alkyl-amino, carbamoyl, sulfamoyl, (C1-C4)-alkoxycarbonyl, (C6-C12)-aryl or (C6-C12) -aryl-(C1-C5)-alkyl, or each of which is optionally substituted one time by (C3-C8)-cycloalkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkylsulfinyl, (C6-C12)-aryl-(C1-C4)-alkylsulfonyl, (C6-C12)-aryl-(C1-C4)-alkylsulfinyl, (C6-C12)-aryloxy, (C3-C9)-heteroaryl or (C3-C9)-heteroaryloxy, and is further optionally substituted one or two times by carboxyl, amino, (C1-C4)-alkylamino, hydroxy, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C5)-alkyl, wherein the heteroaryl is optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl, (C3-C8)-cycloalkyl, carbamoyl, which is optionally substituted on the nitrogen by (C1-C6)-alkyl or (C6-C12)-aryl, or (C6-C12)-aryl, (C6-C12)-aroyl, (C6-C12)-arylsulfonyl, (C3-C9)-heteroaryl or (C3-Cg)heteroaroyl, wherein the heteroaryl, aroyl, arylsulfonyl and heteroaroyl are each independently optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylarnino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl,
• R(2) is hydrogen or methyl,
• R(3) is hydrogen or (C1-C6)-alkyl, wherein the alkyl is optionally monosubstituted by amino, substituted amino, hydroxy,.carbamoyl, guanidino, substituted guanidino, ureido, mercapto, methyl-mercapto, phenyl, 4-chlorophenyl, 4-flubrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, wherein the substituted amino is —NH—A′— and the substituted guanidino is —NH—C(NH)—NH—A′—, wherein A′ is hydrogen, (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C1-C8)-alkoxycarbonyl or (C1-C8)-alkylsulfonyl, each of which is optionally substituted one, two or three times by carboxyl, amino, (C1-C4)-alkyl, (C1-C4)-alkyl-amino, hydroxy, (C1-C3)-alkoxy, halogen, di-(C1-C4)-alkyl-amino, carbamoyl, sulfamoyl, (C1-C4)-alkoxycarbonyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C5yalkyl, or each of which is optionally substituted one time by (C3-C8)-cycloalkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkylsulfinyl, (C6-C12)-aryl-(C1-C4)-alkylsulfonyl, (C6-C12)-aryl-(C1-C4)-alkylsulfinyl, (C6-C12)-aryloxy, (C3-Cgyheteroaryl or (C3-C9)-heteroaryloxy, and is further optionally substituted one or two times by carboxyl, amino, (C1-C4)-alkylamino, hydroxy, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl or ( C6-C12yaryl-(C1-C5-alkyl, wherein the heteroaryl is optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (Q1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl, (C3-C8)-cycloalkyl, carbamoyl, which is optionally substituted on the nitrogen by (C1-C6)-alkyl or (C6-C12)-aryl, or (C6-C12)-aryl, (C6-C12)-aroyl, (C6-C12)-arylsulfonyl, (C3-C9)-heteroaryl or (C3-C9)-heteroaroyl, wherein the heteroaryl, aroyl, arylsulfonyl and heteroaroyl are each independently optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl;
• B is Arg, Lys, Orn, 2,4-diaminobutyroyl or L-homo-arginine, wherein the amino or the guanidino group of the side chain of Arg, Lys, Orn, 2,4-diaminobutyroyl or L-homo-arginine is independently optionally substituted by hydrogen, (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C1-C8)-alkoxycarbonyl or (C1-C8)-alkylsulfonyl, each of which is optionally substituted one, two or three times by carboxyl, amino, (C1-C4)-alkyl, (C1-C4)-alkyl-amino, hydroxy, (C1-C3)-alkoxy, halogen, di-(C1-C4)-alkyl-amino, carbamoyl, sulfamoyl, (C1-C4)-alkoxycarbonyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C5)-alkyl, or each of which is optionally substituted one time by (C3-C8)-cycloalkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkylsulfinyl, (C6-C12)-aryl-(C1-C4)-alkylsulfonyl, (C6-C12)-aryl-(C1-C4)-alkylsulfinyl, (C6-C12)-aryloxy, (C3-C9)-heteroaryl or (C3-C9)-heteroaryloxy, and is further optionally substituted one or two times by carboxyl, amino, (C1-C4)-alkylamino, hydroxy, (C1-C4)alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C5)-alkyl, wherein the heteroaryl is optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl, (C3-C8)-cycloalkyl, carbamoyl, which is optionally substituted on the nitrogen by (C1-C6)-alkyl or (C6-C12)-aryl, or (C6-C12)-aryl, (C6-C12)-aroyl, (C6-C12)-arylsulfonyl, (C3-C9)-heteroaryl or (C3-C9)heteroaroyl, wherein the heteroaryl, aroyl, arylsulfonyl and heteroaroyl are each independently optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkyiamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl;
• X is of formula IIIa or IIIb
• G′-G′-Gly (IIIa)
• G′—NH—(CH2)n—CO (IIIb)
• wherein G′ independently of one another is of formula IV
• wherein R(4) and R(5) together with the atoms they connect to form a heterocyclic mono-, bi- or tricyclic ring having 2 to 15 carbon atoms, and n is 2 to 8;
• E is phenylalanine optionally substituted by halogen in the 2-, 3- or 4-ring position, tyrosine, O-methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine;
• F is covalent bond, or neutral, acidic or basic aliphatic or aromatic amino acid, which is optionally substituted in the side chain;
• (D)-TIC is of formula V
• G is G′ or a covalent bond;
• F′ is covalent bond, —NH—(CH2)n— wherein n is 2-8, or basic amino acid Arg or Lys in the L or D form, wherein the guanidino group or amino group of the side chain of the Arg or Lys is optionally substituted by hydrogen,
• (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C1-C8)-alkoxycarbonyl or (C1-C8)-alkylsulfonyl, each of which is optionally substituted one, two or three times by carboxyl, amino, (C1-C4)-alkyl, (C1-C4)-alkyl-amino, hydroxy, (C1-C3)-alkoxy, halogen, di-(C1-C4)-alkyl-amino, carbamoyl, sulfamoyl, (C1-C4)-alkoxycarbonyl, (C6-C12)-aryl or ( C6-C12)-aryl-(C1-C5)-alkyl, or each of which is optionally substituted one time by (C3-C8)-cycloalkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkylsulfinyl, (C6-C12)-aryl-(C1-C4)-alkylsulfonyl, (C6-C12)-aryl-(C1-C4)-alkylstilfinyl, (C6-C12)-aryloxy, (C3-C9heteroaryl or (C3-C9)-heteroaryloxy, and is further optionally substituted one or two times by carboxyl, amino, (C1-C4)-alkylamino, hydroxy, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C5)-alkyl, wherein the heteroaryl is optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl, (C3-C8)-cycloalkyl, carbamoyl, which is optionally substituted on the nitrogen by (C1-C6)-alkyl or (C6-C12)-aryl, or (C6-C12)-aryl, (C6-C12)-aroyl, (C6-C12)-arylsulfonyl, (C3-C9)-heteroaryl or (C3-C9)heteroaroyl, wherein the heteroaryl, aroyl, arylsulfonyl and heteroaroyl are each independently optionally substituted one, two, three or four times by carboxyl, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl or (C1-C4)-alkoxycarbonyl;
• I is —OH, —NH2 or NHC2H5;
• K is covalent bond or —NH—(CH2)x—CO, wherein x is 1 to 4;
• and
• M is covalent bon, or neutral, acidic or basic aliphatic or aromatic amino acid, which is optionally substituted in the side chain;
• or its physiologically tolerable salts thereof.