TRIFUNCTIONAL ANTITHROMBIN AND ANTIPLATELET PEPTIDES

摘要

Compounds of the formula: X-A-B-C-Y wherein X is an amino terminal residue selected from hydrogen, one or two alkyl groups of from 1 to 6 carbon atoms, one or two acyl groups of from 2 to 10 carbon atoms, carbobenzyloxy, H2NC(=NH)-, or a t-butyloxy carbonyl group; A is a peptide analog of the formula: A1-A2-A3 wherein A1 is (D)Phe, (D)Phg, (D)1-Tiq, (D)3-Tiq, N-Me- (D)Phe, (D)Cha, (D)Chg, (D)Nag, or (D)Thg; A2 is Pro, Pip, or Azt; A3 is Arg, Lys, Orn, or hArg; B is a peptide analog of formulae (3) or (4) wherein B1 is Gly, Ala, (D)Ala, Val, (D)Val, or Gly-Gly; B2 is Gly, Gly-Gly, Gly-Gly-Gly, Gly-Gly-Gly-Gly or any (D) amino acid; B2' is Arg-Ile-Pro or Lys-Ile-Pro; B3 is Arg, hArg, N-Me-Arg or Lys; B4 is Nle, Phe, Met or Cha; C is a peptide analog of the formula: Asp-C1-C2-C3-C4-C5-C6-C7-C8-C9 wherein C1 is Phe, pC1Phe, pNO2Phe, Tha, Npa, Tyr or Trp; C2 is Glu or Asp; C3 is any amino acid; C4 is Ile, Val, Leu or Phe; C5 is Pro, Hyp, Sar, NMePgl or D-Ala; C6 is any amino acid; C7 is any amino acid; C8 is Tyr, Glu, Pro, Ala-Cha, Tyr-Cha, Tyr-Leu and Ala-Tyr; C9 is a bond or is Glu, (D)Glu, Gln, Pro, Leu-Gln, Asp-Glu, or Leu-Pro; and Y is a carboxy terminal residue selected from OH, C1-C6 alkoxy, amino, mono- or di-(C1-C4) alkyl substituted amino, or benzylamino; or pharmaceutically acceptable salts thereof are useful anticoagulant agents. This invention also relates to the use of the above compounds in treating acute postangioplasty occlusion, extracorporeal circulation-induced cytopenia, developing myocardial infarction, and post fibrinolytic therapy occlusion.