Patent DE-10146632-A1 (DE)
Title: New peptide compounds containing upto 6 aminoacid residues, are potent and specific thrombin inhibitors used for treating and diagnosing diseases associated with thrombin
Inventor: THUERK MARCEL
IPC: C07K7/06
Filed: 2001-09-21
Abstract: Peptide compounds (I), containing upto 6 aminoacid residues, are new. Peptide compounds of formula Y 1>-(NH-X 1>-CO)-(NH-X 2>-CO)-(NH-X 3>-CO)-(NH-X 4>-CO)-(NH-X 5>-CO)-(NH-X 6>-CO)-Y 2>(I), their derivatives truncated by at least one aminoacid at the C- and/or N-terminal and salts, are new. Y 1H, Me, acetyl or a group having a 1-32C chain as backbone; NH-X 1-CO : basic aminoacid residue, preferably Arg, Lys or Orn; NH-X 2-CO : cyclic, non-polar aminoacid residue, preferably cyclohexylalanine (Cha) or cyclohexylglycine; NH-X 3-CO : any aminoacid residue, preferably Nle, Leu, Ile, Cha, cyclohexylglycine, Pro, Asp or Glu; NH-X 4-CO : cyclic aminoacid residue, preferably Cha, cyclohexylglycine, Tyr or Phe; NH-X 5-CO : aminoacid residue with a polar side-chain, preferably Gln, Orn, Glu, Arg, Lys, Asn or Asp, or is replaced by a direct bond; NH-X 6-CO : any aminoacid residue, preferably Arg, or is replaced by a direct bond; Y 2OH (C-terminal carboxy group), NH 2(C-terminal amide group), H (C-terminal aldehyde group), 7-amido-4-methyl-coumarin (bonded via the carboxy group), p-nitroanilide (bonded via the carboxy group) or the residue of a compound with a 1-35 atom chain; all aminoacid residues are in L- or D-isomer form. In alternative definitions of the substituents of (I), Y 1and Y 2are as above and: (a) NH-X 1-CO : any aminoacid residue, preferably Val, Ala, Leu, Ile, Nle, Asp, Glu, Ser, Thr, Tyr, Arg, Lys or Orn, or is replaced by a direct bond; NH-X 2-CO : any aminoacid residue, preferably Ala, Val, Leu, Ile, Nle, Ser, Thr, Tyr, Pro, citrulline, Arg, Lys, Orn, Cha or cyclohexylglycine, or is replaced by a direct bond; NH-X 3-CO : any aminoacid residue, preferably Cha or cyclohexylglycine; NH-X 4-CO : small aminoacid residue, preferably Pro, or is replaced by a direct bond; NH-X 5-CO : any aminoacid residue, preferably Tyr or Phe, or is replaced by a direct bond; NH-X 6-CO : basic aminoacid residue, preferably Arg, Lys or Orn; (b) NH-X 1-CO : as in (a); NH-X 2-CO : any aminoacid residue, preferably Ala, Val, Leu, Ile, Nle, Ser, Thr, Tyr, Pro, citrulline, Arg, Lys, Orn, His, Glu, Asp, Trp, Cha or cyclohexylglycine, or is replaced by a direct bond; X 3-X 6as in (a); (c) X 1-X 3as in (b); NH-X 4-CO : small aminoacid residue, preferably Pro or azetidine-2-carboxylic acid; NH-X 5-CO : aromatic aminoacid residue, preferably Tyr or Phe; NH-X 6-CO : basic aminoacid residue, preferably Arg, Lys, Orn or homoarginine; (d) NH-X 1-CO : any aminoacid residue, preferably Val, Ala, Leu, Ile, Nle, Asn, Gln, Ser, Thr, Tyr, Arg, Lys, Orn, Phe, dichlorophenylalanine, tetrahydronorharman-3-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 4-phenyl-piperidine-4-carboxylic acid, thienylalanine, phenylglycine or p-nitirophenylalanine, or is replaced by a direct bond; X 2as in (b); X 3as in (a), and X 4-X 6as in (c); all aminoacid residues are in L- or D-isomer form. ACTIVITY : Anticoagulant; Thrombolytic; Vasotropic; Antiarteriosclerotic; Antiinflammatory; Cytostatic; Neuroprotective. MECHANISM OF ACTION : Thrombin inhibitor. N-Acetyl-L-Phg-D-Cha-L-Aze-D-Tyr-L-Har-amide (Ia) inhibited thrombin by 95% at a concentration of 250 nM.