Thrombin inhibitors based on the amino acid sequence of hirudin

A peptide derivative having the following formula VI:

• ##STR39## wherein X is a hydrophobic group;
• B is a residue of a hydrophobic amino acid;
• W is H, or a branched or straight chain alkyl, aryl or aralkyl radical;
• D is a linear carbon chain having 2 to 4 carbon atoms which can be substituted by lower alkyl, or D is a p-phenylmethyl or a p-phenylethyl group;
• Y is carbonyl, hydroxymethyl of either D or L configuration or --CH.sub.2 --;
• Z is a divalent straight chained link moiety that having a chain length of at least about 10 atoms, in the case where Y is carbonyl or hydroxymethyl, the atom adjacent to the carbon atom of Y may be unsubstituted or mono- or di-fluoro-substituted, and Z can be composed of a carbon chain that is interrupted by one or more O, S, NH, carbonyl, ester or amide groups and can be substituted by one or more substituents selected from alkyl, alkoxy, alkoxyalkyl, aryl and aralkyl groups that can in turn be substituted by amide, hydroxy, imidazol, carboxy or halogen groups, the terminal atom of the chain being a carbon atom that is part of a carbonyl group that forms a peptide linkage with the L-.alpha.-amino acid G.
• G and G' are the same or different and are an L-.alpha.-amino acid having a pk value of about 5 or below;
• X' is a hydrophobic L-.alpha.-amino acid;
• Q is a residue of a L-.alpha.-amino acid or a cyclic L-imino acid;
• W' is H, or a branched or straight chain alkyl, aryl or aralkyl radical;
• R is a hydrophobic group comprising 1 to 5 amino acids or an alkyl, aryl, or aralkyl radical which can be substituted by a carboxyl or amide function or, ##STR40## substituted at the para position of the phenyl ring;
• or R and R' are the same or different and are an amino acid or an amine group having the following formula:
• ##STR41## wherein R.sub.2 and R.sub.3 are each independently hydrogen, lower alkyl, aryl or alkoxyalkyl, and may be joined to form a ring of 5-6 members, which ring can optionally contain an additional heteroatom selected from O, S, and NH, and pharmaceutically acceptable salts thereof, or
• R' is a hydroxyl group attached to Leu to form a carboxyl group, or a therapeutically acceptable salt thereof.

A thrombin inhibitor selected from the group consisting of:

• P536 (SEQ ID NO:11):
• (D-Cha)-Pro-Arg-CH.sub.2 N(COCH.sub.3)CH.sub.2 (CO)-(Gly).sub.4 -DYEPIPEEY-(Cha)-D-OH;
• P617 (SEQ ID NO:20) (BCH-2772):
• H-(D-Phe)-Pro-Arg-CH.sub.2 SCH.sub.2 (CO)-(Gly).sub.4 -DFEEPIEEYLQ-OH;
• and
• P618 (SEQ ID NO:21):
• Ac(D-Phe)-Pro-Arg-CH.sub.2 SCH.sub.2 (CO)-(Gly).sub.4 -DFEEPIPEEYLQ-OH.

A thrombin inhibitor selected from the group consisting of:

• P574 (SEQ ID NO:12):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-(Gly).sub.4 -DFEEIPEEYLQ-OH;
• P596 (SEQ ID NO:13) (BCH-2773):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-(GLY).sub.4 -DYEPIPEEACha-(D)Glu-OH;
• P597 (SEQ ID NO:14):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-(Gly).sub.4 -DFEEIPEEYLQ-OH;
• P603 (SEQ ID NO:15):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-Abu-Gly-DYEPIPEEA-(Cha)-)D-Glu)-OH;
• P604 (SEQ ID NO:16):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-Ava-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH;
• P605 (SEQ ID NO:17):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-Aca-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH;
• P606 (SEQ ID NO:18) (BCH-2774):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-Aha-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH;
• P609 (SEQ ID NO:19):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-(Gly).sub.4 -DYEPIPEEA-(Cha)-(D-Glu)-OH;
• P658 (SEQ ID NO:22):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-NH(CH.sub.2).sub.2 CO-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH;
• P659 (SEQ ID NO:23):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-Gly-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH;
• P660 (SEQ ID NO:24):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-NH(CH.sub.2).sub.3 CO-DYEPIPEEA-(Cha)-(D-Glu)-OH;
• and
• P661 (SEQ ID NO:25):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-NH(CH.sub.2).sub.2 CO-DYEPIPEEA-(Cha)-(D-Glu)-OH.

A thrombin inhibitor selected from the group consisting of:

• P183 (SEQ ID NO:5):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --(CO)]-DFEPIPL-OH;
• P184 (SEQ ID NO:6) (BCH-1710):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --(CO)].sub.2 -DFEPIPL-OH;
• P185 (SEQ ID NO:7):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --(CO)].sub.3 -DFEPIPL-OH;
• BCH-2414 (SEQ ID NO:27):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --(CO)].sub.2 -DEFPIPY-OH;
• BCH-2739 (SEQ ID NO:29):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--(CH.sub.2).sub.4 (CO)].sub.2 -DFEPIPL-OH;
• BCH-2757 (SEQ ID NO:30):
• alpha-N-(Ac)(D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--(CH.sub.2).sub.4 (CO)]-NGDFEPIPL-TFA salt;
• BCH-2758 (SEQ ID NO:31):
• (D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--(CH.sub.2).sub.4 (CO)].sub.2 -DF-(4-thiahomoGlu)-PIPL-TFA salt;
• and
• BCH-2763 (SEQ ID NO:32):
• (D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--(CH.sub.2).sub.4 (CO)].sub.2 -DFEPIPL-TFA salt.

A thrombin inhibitor selected from the group consisting of:

• P79 (SEQ ID NO:1) (BCH-1709):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.2 (CO)-QSHNDGDFEEIPEEYLQ-OH;
• P103 (SEQ ID NO:3):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)-QSHNDGDFEEIPEEYLQ-OH;
• P311 (SEQ ID NO:9) (BCH-1721):
• Ac(D-Cha)-Pro-Arg-(CH.sub.2).sub.2 (CO)-QSHNDGDFEEIPEEYLQ-OH;
• P314 (SEQ ID NO:10) (BCH-1726):
• Ac(D-Cha)-Pro-Arg-(CH.sub.2).sub.2 (CO)-QSHNDGDFEPIPEEY-(Cha)-Q-OH;
• BCH-2408 (SEQ ID NO:26):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.2 (CO)-QSHNDGDFEPIPEEY-(Cha)-Q-OH;
• BCH-2414 (SEQ ID NO:27):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --(CO)].sub.2 -DEFPIPY-OH;
• BCH-2423 (SEQ ID NO:28):
• succinyl(D-Phe)-Pro-Arg-(CH.sub.2).sub.2 (CO)-QSHNDGDFEEIPEEYLQ-OH;
• BCH-2763 (SEQ ID NO:32):
• (D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--(CH.sub.2).sub.4 (CO)].sub.2 -DFEPIPL-TFA salt;
• P596 (SEQ ID NO:13) (BCH-2773):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-(GLY).sub.4 -DYEPIPEEACha-(D)Glu-OH;
• and
• P606 (SEQ ID NO:18) (BCH-2774):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-Aha-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH.

A thrombin inhibitor selected from the group consisting of:

• P314 (SEQ ID NO:10) (BCH-1726):
• Ac(D-Cha)-Pro-Arg-(CH.sub.2).sub.2 (CO)-QSHNDGDFEPIPEEY-(Cha)-Q-OH;
• BCH-2408 (SEQ ID NO:26):
• Ac(D-Phe)-Pro-Arg-(CH.sub.2).sub.2 (CO)-QSHNDGDFEPIPEEY-(Cha)-Q-OH;
• BCH-2763 (SEQ ID NO:32):
• (D-Phe)-Pro-Arg-(CH.sub.2).sub.4 (CO)--[NH--(CH.sub.2).sub.4 (CO)].sub.2 -DFEPIPL-TFA salt;
• P596 (SEQ ID NO:13) (BCH-2773):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-(GLY).sub.4 -DYEPIPEEACha-(D)Glu-OH;
• and
• P606 (SEQ ID NO:18) (BCH-2774):
• (D-Cha)-Pro-Arg-CH.sub.2 (4-pyridylacetyl)-Aha-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH.