Integrin-Mediated drug targeting

Conjugate according to one of the preceding claims, characterized by the formula (I)

• CT-AA1-AA2-AA3-AA4-Sp-IA (I)
• in which
• CT denotes a cytotoxic radical or a radical of a cytostatic or of a cytostatic derivative, which can additionally carry a hydroxyl, carboxyl or amino group,
• AA1 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp′,
• AA2 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp′,
• AA3 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp′,
• AA4 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp′,
• in which
• Sp′ is an arylaminocarbonyl or an arylaminothiocarbonyl radical having 7-11 carbon atoms,
• Sp is absent, is an arylaminocarbonyl or an arylaminothiocarbonyl radical having 7-11 carbon atoms or is an alkanedicarboxylic acid radical having 3 to 8 carbon atoms or a carbonyl or a thiocarbonyl radical,
• with the proviso that at least one of the radicals AA1 to AA4 and/or Sp is present,
• IA is a non-peptide radical addressing an αvβ3 integrin receptor, which is selected from the group consisting of
• A) a radical of the formula (II)
• in which
• R1 is OH, a substituted or unsubstituted alkoxy or cycloalkoxy radical, a substituted or unsubstituted aryloxy radical or a saturated or unsaturated, optionally substituted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (II) is bonded to the rest of the conjugate;
• R2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl radical or an optionally substituted alkinyl radical, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate, or is —NR2′2, —NR2′SO2R2″, —NR2′COOR2″, —NR2′COR2′, —NR2′CONR2′2 or —NR2′CSNR2′2;
• in which
• R2′ independently of one another is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, or optionally represents a direct bond, via which the radical of the formula (II) is bonded to the rest of the conjugate;
• R2″ is a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate;
• U is a direct bond or a substituted or unsubstituted alkylene group, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate;
• V is a substituted or unsubstituted alkylene group, —NR2′CO— or —NR2′SO2—, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate;
• A and B each independently of one another is a 1,3- or 1,4-bridged, optionally additionally substituted phenylene group;
• W is a direct bond or a substituted or unsubstituted alkylene group;
• C is absent or is
• R3 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R4, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic ring system, which includes the nitrogen atom to which R3 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
• R4 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R3, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms, or optionally represents a direct bond, via which the radical of the formula (II) is bonded to the rest of the conjugate;
• X is O, N or S;
• m is 0 or 1;
• Y is a direct bond or an optionally substituted alkylene or alkine group;
• R5 is absent, —NO2, —CN, —COR5′, —COOR5′, or is bonded to one of R3, Y, R4 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
• R5′ is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical which can be saturated or unsaturated and/or can contain further heteroatoms;
• R6 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R3, R4, Y or R5, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
• or
• B) a radical of the formula (III)
• in which
• R7 is OH, a substituted or unsubstituted alkoxy or cycloalkoxy radical, a substituted or unsubstituted aryloxy radical or a saturated or unsaturated, optionally substituted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (III) is bonded to the rest of the conjugate;
• R8 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl radical, an optionally substituted alkinyl radical, a hydroxyl radical or an alkoxy radical or is bonded to R9 with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes the carbon atom to which R8 is bonded and can optionally contain heteroatoms;
• R9 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl radical, an optionally substituted alkinyl radical, a hydroxyl radical or an alkoxy radical or is bonded to R8 with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes the carbon atom to which R9 is bonded and can optionally contain heteroatoms;
• R10 is —SO2R10′, —COOR10″, —COR10′, —CONR10′2 or —CS—NR10′2, or represents a direct bond via which the radical of the formula (III) is optionally bonded to the rest of the conjugate;
• R10′ independently of one another is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, via which the radical of the formula (III) is optionally bonded to the rest of the conjugate;
• R10″ is a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, via which the radical of the formula (III) is optionally bonded to the rest of the conjugate;
• R11 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical or a substituted or unsubstituted aryl radical,
• R16 is hydrogen, CN, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted alkoxy radical or a halogen atom;
• R17 is hydrogen, CN, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted alkoxy radical or a halogen atom;
• L is —(CH2)nNHSO2(CH2)o—, —(CH2)nSO2NH(CH2)o—, —(CH2)nNH—CO(CH2)o—, —(CH2)nCONH(CH2)o—, —(CH2)nOCH2(CH2)o—, —(CH2)nCH2O(CH2)o—, —(CH2)nCOO(CH2)o—, —(CH2)nOOC—(CH2)o—, —(CH2)nCH2CO(CH2)o—, —CH2)nCOCH2(CH2)o—, —NHCONH—, —(CH2)nSCH2(CH2)o—, —(CH2)nCH2S(CH2)o—, —(CH2)nCH2SO(CH2)o—, —(CH2)nSOCH2(CH2)o—, —(CH2)nCH2SO2(CH2)o— or —(CH2)nSO2CH2(CH2)o—, where n and o each is an integer of 0 or 1 and n+o≦1;
• R12 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R13, R14 or R15, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom, to which R12 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
• X′ is N, O or S;
• p is 0 or 1;
• R13 is absent, is —H, a substituted or unsubstituted alkyl or cycloalkyl radical, —NO2, —CN, —COR13′, —COOR13′, or is bonded to one of R12, R14 or R15 with formation of an optionally substituted heterocyclic ring system which includes X′ and can be saturated or unsaturated and/or can contain further heteroatoms;
• R13′ is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical which can be saturated or unsaturated and/or can contain further heteroatoms;
• Y′ is N or S;
• R14 is absent, hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R12, R13 or R15, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R14 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
• R15 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R12, R13 or R14, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R15 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms, or optionally represents a direct bond via which the radical of the formula (III) is bonded to the rest of the conjugate;
• or
• C) a radical of the formula (IV)
• in which
• R18 is OH, a substituted or unsubstituted alkoxy or cycloalkoxy radical, a substituted or unsubstituted aryloxy radical or a saturated or unsaturated, optionally substituted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (IV) is bonded to the rest of the conjugate;
• q is 0 or 1;
• R19 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an alkylamine radical, an alkylamide radical, or optionally represents a direct bond, via which the radical of the formula (IV) is bonded to the rest of the conjugate;
• and their physiologically acceptable salts and stereoisomers.