Method for the synthesis of penta-pendant enantiomer-pure chelators and process for therapeutically active bioconjugates preparation by a covalent binding thereof

A pentapendant enantiomer-pure chelator represented by the structure (VII):

• wherein
• X1-X5, Y1-Y5, Z1-Z5 are each individually hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl or cycloalkyl, substituted or unsubstituted aryl or heteroaryl, especially O-substituted or unsubstituted carboxyl, nitrile, N-substituted or unsubstituted carboxamide, formyl, N-hydroxyiminomethyl, independently O- and N-substituted or unsubstituted N-hydroxyaminocarbonyl, phosphonyl, phosphinyl, alkylphosphonyl, alkylphosphonyl, arylphosphonyl, arylphosphonyl forming pendants,
• R1, R2, R3, R4 are groups forming an adequate enantiomer (R,R), (R,S), (S,R) or (S,S) wherein R1, R2, R3, R4 are independently hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl or cycloalkyl, substituted or unsubstituted aryl or heteroaryl, especially 4-substituted benzyl of the structure (VIII)
• Q1, Q2 are each individually hydrogen, substituted or or unsubstituted C1-C24 alkyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted carboxyl or N-substituted or unsubstituted carboxamide;
• Sp is spacing group of the formula
• n is 0 or 1;
• G is hydrogen, substituted or unsubstituted C1-C24 alkyl or C2-C24 alkenyl, N-substituted or unsubstituted amine, N-substituted or unsubstituted hydrazine, hydroxyl, O-alkylhydroxyl, O-acylhydroxyl, thiol, S-alkylthiol, O-substituted or unsubstituted carboxyl, N-substituted or unsubstituted carboxamide, isocayanate, isothiocyanate, carboxamidine, carbohydrazide, nitro, nitroso, formyl, formyl forming cyclic or uncyclic acetal, acetyl, 2-haloacetyl, halomethyl, hydroxymethyl or dihydroxyboronyl;
• or is a linker of the formula
• A
• or
• B
• or
• C
• or
• A-B-(C)a
• or
• A1-B-A2-(C)a
• or
• A1-A2-A3-(C)a
• or
• A1-A2-A3-A4-(C)a
• or
• A1-(A)β-A3-(C)a
• or
• A1-B1-(A2-B2)γ-A3-B3-(C)a
• wherein β, γ are each individually from 0 to 24;
• α is 0 or 1;
• wherein A1, A2, A3,
• A4 are independently fragments of structure A;
• B1, B2 are independently fragments of structure B;
• wherein A is a fragment of structure (IX)
• wherein j, k, m, n, o, p are each individually from 0 to 12;
• Het1-Het4 are independently O, S, NRHet, wherein RHet is hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted aryl;
• X1-X4 are each individually hydrogen, substituted or unsubstituted primary C1-C12 alkyl or cycloalkyl, substituted or unsubstituted aryl, hydroxyl, alkoxyl, aryloxyl, halogen, substituted or unsubstituted amine, carboxyl, N-substituted or unsubstituted carboxamide, nitrile, alkoxycarbonyl;
• or wherein X1-X4 can form mutually 5-membered and 6-membered saturated or unsaturated cycles, aromatic cycles and heterocycles;
• or X1-X4 can form mutually and each individually an oxo group, or a double and triple bond between C1 and C2;
• wherein B is fragment of structure (X)
• wherein q, r, s, t, u are each individually from 0 to 12;
• Het5 is independently O, S, NRHet, wherein RHet is hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted aryl;
• X5-X12 are each individually hydrogen, primary substituted or unsubstituted C1-C12 or cycloalkyl, substituted or unsubstituted aryl, hydroxyl, alkoxyl, aryloxyl, halogen, substituted or unsubstituted amine, carboxyl, N-substituted or unsubstituted carboxamide, nitrile, alkoxycarbonyl, or X5-X12 can form mutually 5-membered and 6-membered saturated or unsaturated cycles, aromatic cycles and heterocycles, or X5-X12 can form mutually and each individually an oxo group, or one or two double and triple bonds between C1, C2, C3 or C4,
• and wherein C is a reactive group, particularly a structural fragment selected from the group of hydroxyl, carboxyl, amino group, chloroacetyl, bromoacetyl group, iodoacetyl group, carbonyl chloride, carbonyl fluoride, carbonyl bromide, sulphonyl chloride, sulphonyl fluoride, sulphonyl bromide, sulphonyl arylsulphonate, sulphonyl alkylsulphonate, or an active ester, e.g. selected from the group:
• or from the group:
• or a biologically active molecule, especially a biopolymer, which may be a natural substrate present in an organism or its synthetic analog, wherein the molecule preferably has biologic activity in a physiological function, especially in metabolic effect control or reproduction, wherein the biopolymer is preferably a polypeptide, or preferably comprises amino acids, wherein the biologically active molecule is preferably selected from the group consisting of:
• antibodies, e.g. monoclonal antibodies (e.g. antiCD33, antiCD25, antiCD66), antibody fragments, polyclonal antibodies, minibodies, somatostatin and derivatives thereof, IGF-1 (somatomedin) and derivatives thereof, IGF-2, IGF-protein-3, somatostatin-biotin derivatives, tumor-specific proteins and synthetic agents, vascular endothelial growth factor, myoglobins, apomyoglobins, neurotransmitter peptides, octreotide, lanreotide, Somatuline, vapreotide, tumor necrosis factors and peptides that accumulate in inflamed tissues.