LIGANDS FOR INTEGRIN amp;#x26;#945;Vamp;#x26;#946;8, SYNTHESIS AND USES THEREOF

摘要

Disclosed are compounds represented by the following general formula (I): Cyclo-(Arg-Gly-Asp-X¹-X²-X²-X⁴-X⁵) (I) wherein the variables groups X¹ to X⁵ have the following meanings X¹: Leu, Ile, Nle, Val, Tyr, Phe; X²: D-amino acid such as D-Pro, N-Me-D-Phe; X³: Pro, N-Me-amino acid such as N-Me-Lys, N-Me-Lys(Ac); Pro-Rx3, N-Me-Lys-Rx4; X⁴: Gly, Ala, Ser, Thr; X⁵: Leu, Ala, Tyr, His, Ile, Nle, Val, Phe wherein Pro-Rx3 represents a proline residue that carries at the C-3, C-4 or C-5 carbon atom and preferably the C-4 carbon atom a functional group selected from —NH2, —OH, —NH—Ac, —NH-hexyne, and wherein Lys-R^x4 represents a lysine residue, wherein the ω-amino nitrogen atom carries a group of the formula -L4-R4, wherein L4 is selected from the group consisting of covalent bond, —C(O)—, and —C(O)—O—, . . . , and wherein R4 is selected from the group consisting of —(CH2)n-C≡CH with n=0, 1, 2, 3, 4, 5, 6, 7 or 8, or wherein the sub-sequence -X²-X³- represents a β-turn mimetic diffeωωring from the meanings above, or pharmaceutically acceptable salts, esters, solvates, polymorphs or modified forms thereof represented by the following general formula (II): (X⁰)_n1L(X⁸)_n2 wherein X0 represents the compound of the general formula (I) as specified above (excluding one hydrogen atom to allow bonding to the linker), L represents a linker, X⁸ represents the effector moiety and wherein n1 and n2 are each independently selected from the range of 1 to 5, preferably such that each of n1 and n2 represents 1, wherein n1+n2 represents the number of valencies of the linker and is preferably in the range of from 2 to 6, more preferably 2-5, with the proviso that each of n1 and n2 is at least 1, as well as uses therefore in therapy and imaging.