Vitronectin receptor antagonists, their preparation and use

A compound of formula I,

• A—B—D—E—F—G (I)
• in which:
• A═A1 or A2, where
• A1═R2 R3N—C (═NR2) NR2C(O)—, R2 RN—C(═NR2) NR2) NRC(S)—, R2R3N—C (═NR2) NR2—S (O)n—,
• and A2=
• where, in A1 or A2
• is a 5-membered to 10-membered monocyclic or polycyclic, aromatic or nonaromatic ring system which contains the group
• and, in addition, can contain from 1 to 4 heteroatoms selected from the group consisting of N, O and S optionally can be substituted, once or more than once, by R12, R13, R14 and R15;
• B is a direct linkage, (C1-C8)-alkanediyl, —CR2═CR3—, (C5-C10)-arylene, (C3-C8)-cycloalkylene, —C≡C—, which can in each case be substituted, once or twice, by (C1-C8)-alkyl;
• D is a direct linkage, (C1-C8)-alkanediyl, (C5-C10)-arylene —O—, —NR2—, —CO—NR2—, —NR2—CO—, —NR2—C(O)—NR2—, —NR2—C(S)—NR2—, —OC(O)—, —C(O)O—, —CO—, —S(O)—, —S(O)2—S(O)2—NR2—, S(O)—NR2—, —NR2—S(O)—, —NR2—S(O)2—, S—, —CR2═CR3— —C≡C—, —NR2—N═CR2—, —N═CR2, —R2C═N—, —CH(OH)—, which can in each case be substituted, once or twice, by (C1-C8)-alkyl, —CR2═CR2— or (C5-C6)-aryl, where, if B is a direct linkage, D can also be a direct linkage or a radical as defined under D, which radical is substituted once or twice, as described under D, and is linked to B by way of one of these substituents;
• E is
• where R1a, R2a, R20a, R21a and R22a are:
• R1a and R2a are, independently of each other, from one to three groups selected from the series consisting of hydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, hydroxyl, mercapto sulfonamido, and an optionally substituted radical selected from the group consisting of C1-C12-alkyl, C2-C12-alkenyl, C3-C12-alkynyl, C3-C12-cycloalkyl, C6-C14-aryl, C6-C10-aryl-C1-C8-alkyl, C1-C12-alkyloxy, C6-C14-aryloxy and C1-C12-acylamino, where the substituents are a radical selected from the group consisting of halogen, cyano, azido, nitro, hydroxyl, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, C1-C4-alkoxy, phenyl and phenoxy;
• R20a is hydrogen, halogen, C1-C4-alkoxy, C1-C4-alkyl, phenyl, benzyl or halogen-C1-C4-alkyl,
• R21a and R22a are, independently of each other,
• (i) hydrogen
• (ii) (C1-C12)-alkyl
• (iii) (C6-C14)-aryl,
• (iv) (C3-C14)-cycloalkyl,
• (v) (C1-C12)-alkyl-(C6-C14)-aryl;
• (vi) (C1-C12)-alkyl-(C3-C14)-cycloalkyl, where the radicals defined under (ii) to (vi) can be substituted by one or more radicals selected from the group consisting of halogen;
• nitro;
• hydroxyl;
• carboxyl;
• tetrazole;
• hydroxamate;
• sulfonamide;
• trifluoroimide;
• phosphonate;
• C1-C6-alkyl;
• C6-C14-aryl;
• benzyl;
• C3-C14-cycloalkyl;
• COR24a and CONR25R26;
• where
• R24a is a radical selected from the group consisting of C1-C8-alkoxy;
• C3-C12-alkenoxy;
• C6-C12-aryloxy;
• di-C1-C8-acetylamino-C1-C8-alkoxy;
• acylamino-C1-C8-alkoxy;
• acetylaminoethoxy;
• nicotinoylaminoethoxy;
• succinamidoethoxy;
• pivaloylethoxy;
• and C6-C12-aryl-C1-C8-alkoxy, where the aryl group can be optionally substituted by from one to three radicals selected from the group consisting of nitro, halogen, C1-C4-alkoxy, amino, hydroxyl, hydroxy-C2-C8-alkoxy and dihydroxy-C3-C8-alkoxy;
• R25 and R26 are, independently of each other, hydrogen, C1-C10-alkyl, C3-C10-alkenyl, C6-C14-aryl or C1-C6-alkyl-C6-C10-aryl, or
• R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;
• or
• (vii) Q2—L3, where
• Q2 is hydrogen or Q1;
• and
• L3 is a direct linkage, L1 or L2;
• Q1 is a substituted or unsubstituted, positively charged, nitrogen-containing radical,
• L1 is a divalent radical which contains from 3 to 9 methylene groups, where from one to all the methylene groups can be replaced with one or more alkene groups, alkyne groups, aryl groups or functional groups containing heteroatoms selected from the group consisting of N, O and S, and
• L2 is an optionally substituted, divalent radical;
• and R22b is:
• (i) hydrogen
• (ii) (C1-C12)-alkyl
• (iii) (C6-C14)-aryl
• (iv) (C3-C14)-cycloalkyl
• (v) C1-C2)-alkyl-(C6-C14)-aryl;
• (vi) (C1-C12)-alkyl-(C3-C14)-cycloalkyl, where the radicals defined under (ii) to (vi) can be substituted by one or more radicals from the group consisting of halogen;
• nitro, hydroxyl;
• carboxyl;
• tetrazole;
• hydroxamate;
• sulfonamide;
• trifluoroimide;
• phosphonate, C1-C6-alkyl;
• C6-C14-aryl;
• benzyl;
• C3-C14-cycloalkyl;
• COR24a and CONR25R26;
• where
• R24a is a radical selected from the group consisting of C1-C8-alkoxy;
• C3-C12-alkenoxy;
• C6-C12-aryloxy;
• di-C1-C8-alkylamino-C1-C8-alkoxy;
• acylamino-C1-C8-alkoxy;
• acetylaminoethoxy;
• nicotinoylaminoethoxy;
• succinamidoethoxy;
• pivaloylethoxy;
• and C6-C12-aryl-C1-C8-alkoxy, where the aryl group can optionally be substituted by from one to three radicals selected from the group consisting of nitro, halogen, C1-C4-alkoxy, amino, hydroxyl, hydroxy-C2-C8-alkoxy and dihydroxy-C3-C8-alkoxy;
• R25 and R26 are, independently of each other, hydrogen, C3-C10-alkyl, C3-C10-alkenyl, C6-C14-aryl or C1-C6-alkyl-C6-C10-aryl, or
• R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;
• (vii) Q2—L3, where
• Q2 is hydrogen or Q1;
• and
• L3 is a direct linkage, L1 or L2;
• Q1 is a substituted or unsubstituted, positively charged, nitrogen-containing radical;
• L1 is a divalent radical which contains from 3 to 9 methylene groups, where from one to all the methylene groups can be replaced with one or more alkene radicals, alkyne radicals, aryl radicals or functional groups containing heteroatoms selected from the group consisting of N, O and S, and
• L2 is an optionally substituted, divalent radical;
• F is defined like D;
• and
• G is
• where
• R2 and R3 are, independently of each other, hydrogen, (C1-C10)-alkyl, which is optionally substituted, once or more than once, by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkyl, R8OC(O)R9, R8R8NC(O)R9 or R8C(O)R9;
• R4, R5, R6 and R7 are, independently of each other, hydrogen, fluorine, OH, (C1-C8)-alkyl, (C3-C14)-cycloalkyl, (C3-C14)-cycloalkyl-(C1-C8)-alkyl, or R8OR9, R8SR9, R8CO2R9, R8OC(O)R9, R8-(C5-C14)-aryl-R9, R8N(R2)R9, R8R8NR9, R8N(R2)C(O)OR9,R8S(O)nN(R2)R9, R8OC(O)N(R2)R9, R8C(O)N(R2)R9, R8N(R2)C(O)N(R2)R9, R8N(R2)S(O)nN(R2)R9, R8S(O)nR9, R8SC(O)N(R2)R9, R8C(O)R9, R8N(R2)C(O)R9 or R8N(R2)S(O)nR9;
• R8 is hydrogen, (C1-C8)alkyl, (C3-C14)-cycloalkyl, (C3-C14)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl or (C5-C14)-aryl-(C1-C8)-alkyl, where the alkyl radicals can be substituted, once or more than once, by fluorine;
• R9 is a direct linkage or (C1-C8)-alkanediyl;
• R10 is C(O)R11, C(S)R11, S(O)nR11, P(O)(R11)2 or a four-membered to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S;
• R11 is OH, (C1-C8)-alkoxy, (C5-C14)-aryl-(C1-C8)-alkoxy, (C5-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C4)-alkoxy, (C5-C14)-aryl-(C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, NH2, mono- or di-((C1-C8)-alkyl)-amino, (C5-C14)-aryl-(C1-C8)-alkylamino, (C1-C8)-dialkylaminocarbonylmethyloxy, (C5-C14)-aryl-(C1-C8)-dialkylaminocarbonylmethyloxy or (C5-C14)-arylamino or the radical of an L-amino acid or D-amino acid;
• R12, R13, R14 and R15 are, independently of each other, hydrogen, (C1-C10)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkyl, H2N, R8ONR9, R8OR9, R8OC(O)R9, R8R8NR9, R8-(C5-C14)-aryl-R9, HO-(C1-C8)-alkyl-N(R2)R9, R8N(R2)C(O)R9, R8C(O)N(R2)R9, R8C(O)R9, R2R3N—C(═NR2)—NR2, R2R3N—C(═NR2), ═O, or ═S;
• where two adjacent substituents from R12, R13, R14, and R15 can also together be —OCH2O—, —OCH2CH2O— or —OC(CH3)o—;
• n is 1 or 2;
• p and q are, independently of each other, 0 or 1;
• in all its stereoisomeric forms and mixtures thereof in all proportions, and its physiologically tolerated salts.