Beta-hairpin peptidomimetics as CXC4 antagonists

摘要

β-Hairpin peptidomimetics of the general formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Xaa13-Xaa14-DPro15-Pro16-), disulfide bond between Cys4 and Cys11, and pharmaceutically acceptable salts thereof, with Xaa3, Xaa7, Xaa8, Xaa13 and Xaa14 being amino acid residues of certain types which are defined in the description and the claims, have favorable pharmacological properties and can be used for preventing HIV infections in healthy individuals or for slowing and halting viral progression in infected patients; or where cancer is mediated or resulting from CXCR4 receptor activity; or where immunological diseases are mediated or resulting from CXCR4 receptor activity; or for treating immunosuppression; or during apheresis collections of peripheral blood stem cells and/or as agents to induce mobilization of stem cells to regulate tissue repair. These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

主权项

1. A backbone cyclized peptidic compound, built up from 16 amino acid residues, of the formula
cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Xaa13-Xaa14-DPro15-Pro16-)  (I), in which Xaa3 is Ala; Tyr; or Tyr(Me), Tyr(Me) is (2S)-2-amino-(4-methoxyphenyl)-3-propionic acid, Xaa7 is DTyr; DTyr(Me); or DPro, DTyr(Me) is (2R)-2-amino-(4-methoxyphenyl)-3-propionic acid, or, Xaa8 is Dab; or Orn(iPr), Dab is (2S)-2,4-diaminobutyric acid, Orn(iPr) is (2S)-Nω-isopropyl-2,5-diaminopentanoic acid, Xaa13 is Gln; or Glu, Xaa14 is Lys(iPr), Lys(iPr) is (2S)-Nω-isopropyl-2,6-diaminohexanoic acid, all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues, and the two —SH groups in the two L-cysteine residues Cys4 and Cys11 are replaced by one —S—S— group, in free form or in pharmaceutically acceptable salt form.