Thrombin inhibitors based on the amino acid sequence of hirudin

Claim 2

A thrombin inhibitor of formula (I) AS--Y--Z--A (I) and pharmaceutically acceptable salts thereof wherein AS is a hydrophobic moiety which binds the catalytic site of thrombin, said hydrophobic moiety comprising (a) one or two hydrophobic α-amino acids, which are optionally substituted by a lower alkyl, aryl or aralkyl, and (b) a guanidino group; Y is (CO), --CH 2 --, or --CH 2 OH; Z is a divalent, straight chained linker moiety that has a chain length of at least about 10 atoms to about 85 atoms; and A is an acidic portion of formula (III) ##STR30## wherein G and G' are the same or different and are an L-α-amino acid having a pk value of about 5 or below; X' is a hydrophobic L-α-amino acid; Q is an L-α-amino acid or a cyclic L-imino acid; Q 1 and Q 2 are different and are either Ile or Pro; W is H, or a branched or straight chain alkyl, aryl or aralkyl radical, with the proviso that W' is linked to whichever of Q 1 or Q 2 is Pro; R is selected from the group consisting of a hydrophobic amino acid; an alkyl, aryl or aralkyl radical, optionally substituted by a carboxyl or amide function; Leu-R'; Glu-Glu-Ala-R'; Glu-Glu-Tyr-Leu-Gln-OH; Glu-Glu-Phe-Leu-R'; and J Glu-Glu-Phe-Leu-Glx-R' J wherein J is H, OH, O--SO 2 --OH, --CH 2 --SO 2 --OH or --O--PO 2 --OH, or --CH 2 --PO 2 --OH substituted at the para position of the phenyl ring, or R and R' are the same or different and are a hydroxyl group, an amino acid or an amine group having the following formula (IV): ##STR31## wherein R 2 and R 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 the group consisting of O, S and NH and wherein, with the proviso that A is at least six amino acids in length, any one of G, G', X' and Q optionally are absent; and pharmaceutically acceptable salts thereof.

Claim 3

A thrombin inhibitor according to claim 1, wherein Y is carbonyl.

Claim 4

A thrombin inhibitor according to claim 2, wherein Z is a divalent linker moiety composed of a carbon chain that is interrupted by one or more O, S, or NH, and can be substituted by one or more substituents selected from the group consisting of 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 said acidic portion A and with the proviso that the initial atom of the chain is not a nitrogen atom forming a peptide bond with said Y.

Claim 5

A thrombin inhibitor according to claim 3, wherein Z is --(CH.sub.2).sub.n --(CO).sub.m --E, (II) wherein m is 0 or 1, n is an integer ranging from 0 to 4, E is a carbon chain that is interrupted by one or more O, S, or NH, and can be substituted by one or more substituents selected from the group consisting of 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 said acidic portion A.

Claim 6

A thrombin inhibitor according to claim 4, wherein E is the native hirudin 49-54 sequence or analogs thereof.

Claim 7

A thrombin inhibitor according to claim 4, wherein E is selected from the group consisting of -Gln-Ser-His-Asn-Asp-Gly-, -Gly-Ser-His-Asn-Asp-Gly-, -[5-aminovaleryl] 1-2 , and (Gly) 4 .

Claim 8

A thrombin inhibitor according to claim 3, wherein Z is (CH 2 ) 2-4 (CO)-Gln-Ser-His-Asn-Asp-Gly-.

Claim 9

A thrombin inhibitor according to claim 7, wherein Z is (CH 2 ) 2 (CO)-Gln-Ser-His-Asn-Asp-Gly-.

Claim 10

A thrombin inhibitor according to claim 7, wherein Z is (CH 2 ) 3 (CO)-Gln-Ser-His-Asn-Asp-Gly-.

Claim 11

A thrombin inhibitor according to claim 7, wherein Z is selected from the group consisting of (CH 2 ) 4 (CO)-Gln-Ser-His-Asn-Asp-Gly-.

Claim 12

A thrombin inhibitor according to claim 4, wherein E is a synthetic spanner of the general formula (III): --[NH--L--CO].sub.m -- (III) wherein m is an integer ranging from 1 to 4, and L is a hexapeptide, or saturated or unsaturated alkyl chain corresponding to 18 atoms or less.

Claim 13

A thrombin inhibitor according to claim 11, wherein L is --(CH 0-2 ) n --, wherein n is an integer ranging from 1 to 4.

Claim 14

A thrombin inhibitor according to claim 12, wherein L is --(CH 0-2 ) 4 --.

Claim 15

A thrombin inhibitor according to claim 13, wherein L is --CH 2 --CH 2 --CH 2 --CH 2 --.

Claim 16

A thrombin inhibitor according to claim 13, wherein L is --CH 2 --CH═CH--CH 2 --.

Claim 17

A thrombin inhibitor according to claim 4, wherein Z is (CH 2 ) 4 CO--[NH--CH 2 --CH═CH--CH 2 --CO] 1-3 .

Claim 18

A thrombin inhibitor according to claim 4, wherein Z is (CH 2 ) 4 CO--[NH--CH 2 --CH═CH--CH 2 --CO] 1 .

Claim 19

A thrombin inhibitor according to claim 4, wherein Z is (CH 2 ) 4 CO--[NH--CH 2 --CH═CH--CH 2 --CO] 2 .

Claim 20

A thrombin inhibitor according to claim 4, wherein Z is (CH 2 ) 4 CO--[NH--CH 2 --CH═CH--CH 2 --CO] 3 .

Claim 21

A thrombin inhibitor according to claim 4, wherein E is a carbon chain interrupted by O, NH, or S, and can be substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, and alkoxyalkyl groups that can be substituted in turn by amide, hydroxy, imidazol, carboxy, or halogen groups, wherein said alkyl, alkoxy, and alkoxyalkyl groups can join the carbon chain at two points to form an aromatic or non-aromatic ring within the carbon chain.

Claim 22

A thrombin inhibitor according to claim 20, wherein E is pyridylacetyl-R 15 wherein R 15 is 1-4 amino acids.

Claim 23

A thrombin inhibitor according to claim 21, wherein E is 4-pyridylacetyl-(R 20 ) 0-1 -R 30 wherein R 20 , if present, is a linker of formula (III), --[NH--L--CO] m --, wherein m is 1-6 and R 30 is (Gly) 1-4 .

Claim 24

A thrombin inhibitor according to claim 22, wherein R 20 is not present, and R 30 is (Gly) 2-4 .

Claim 25

A thrombin inhibitor according to claim 1 or 2 wherein said AS portion is: ##STR32## wherein X is a hydrophobic group; B is a residue of a hydrophobic amino acid; W is H or a branched or straight chained alkyl, aryl, or aralkyl radical; D is ρ-phenylmethyl, ρ-phenylethyl, or a linear carbon chain having 2 to 4 carbon atoms which can be substituted by lower alkyl.

Claim 26

A thrombin inhibitor according to claim 24, wherein X is a hydrophobic α-amino acid in the D-configuration, attached by a peptide linkage to B.

Claim 27

A thrombin inhibitor according to claim 25, wherein X is D-Phe, D-4FPhe or D-4ClPhe wherein the α-amino group is neutralized by acetylation or benzoylation.

Claim 28

A thrombin inhibitor according to claim 24, wherein B is a residue of a hydrophobic α-amino acid of the L-configuration or a cyclic imino acid which can bear one or more alkyl substituents attached to the ring, wherein said substituents may bridge to form a cyclic structure; D is ρ-phenylmethyl, ρ-phenylethyl, ethylene, butylene, or propylene; W is hydrogen or a lower alkyl, aryl, or aralkyl substituent.

Claim 29

A thrombin inhibitor according to claim 27 wherein B contains a piperidine or pyrrolidine ring; and W is H or a lower alkyl, aryl, or aralkyl substituent on the 3, 4 or 5 position of the piperidine or pyrrolidine ring of B.

Claim 30

A thrombin inhibitor according to claim 1, wherein X is D-Phe, D-4FPhe or D-4ClPhe; B is valine, pipecolic acid, or proline; W is hydrogen or a lower alkyl, aryl, or aralkyl substituent and may be substituted on the 3, 4, or 5 position of the ring when B is proline or pipecolic acid; D is propylene or ρ-phenylmethyl.

Claim 31

A thrombin inhibitor according to claim 28, wherein X is D-Phe, B is Pro, and D is propylene.

Claim 32

A thrombin inhibitor according to claim 1 wherein G, G', X', and Q are present, Q 1 is Ile and Q 2 is Pro.

Claim 33

A thrombin inhibitor according to claim 1, wherein G and G' are independently Asp, Glu, ##STR33## wherein n is 0 to 2, X' is L-Phe, L-4FPhe, or L-4ClPhe, Phe, Glu, or Tyr; Q is proline, pipecolic acid, sarcosine, or glutamic acid; R is selected from the group consisting of ##STR34## wherein J is H, or OH, substituted at the para position of the phenyl ring; R' is hydroxyl radical of the COOH terminus of the preceding amino acid, a group comprising 1 to 2 amino acid, or an amine group having the following formula: ##STR35## wherein R 2 and R 3 are each independently hydrogen, lower alkyl, aryl, or alkoxyalkyl, or 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, or pharmaceutically acceptable salts thereof.

Claim 34

A thrombin inhibitor according to claim 32, wherein G and G' are independently Asp, or Glu; X' is Phe; Q is proline, pipecolic acid, or Glu; R is selected from the group consisting of ##STR36## wherein J is H, or OH, substituted at the para position of the phenyl ring; R' and R" are hydroxyl radical of the COOH terminus of the preceding amino acid, any amino acid, or an amine group having the following formula: ##STR37## wherein R 2 and R 3 are each independently hydrogen, lower alkyl, aryl, or alkoxyalkyl, or may be joined to form a ring of 5-6 members, which ring can optionally contain an additional heteroatom selected from the group consisting of O, S, and NH, or pharmaceutically acceptable salts thereof.

Claim 35

A thrombin inhibitor according to claim 1, wherein G is Asp, G' is Glu, X' is Phe, Q is Glu or Pro, W' is H, n-butyl, or methyl, and R is Leu-R', ##STR38## wherein J is H, or OH, substituted at the para position of the phenyl ring, and R' and R" are a hydroxyl radical of the COOH terminus of the preceding amino acid, any amino acid, or an amine group or pharmaceutically acceptable salts thereof.

Claim 36

A thrombin inhibitor according to claim 34, wherein R is Glu-Glu-Tyr-Leu-Gln-OH, or Leu-OH, or Glu-Glu-Tyr-Leu-OH.

Claim 37

A thrombin inhibitor according to claim 34, wherein R is Glu-Glu-Tyr-Leu-Gln-OH, or Leu-OH.

Claim 38

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 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-α-amino acid G. G and G' are the same or different and are an L-α-amino acid having a pk value of about 5 or below; X' is a hydrophobic L-α-amino acid; Q is a residue of a L-α-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 2 and R 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.

Claim 39

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 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-α-amino acid G. G and G' are the same or different and are an L-α-amino acid having a pk value of about 5 or below; X' is a hydrophobic L-α-amino acid; Q is a residue of a L-α-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 2 and R 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.

Claim 40

A peptide according to claim 37, wherein X is a hydrophobic α-amino acid in the D-configuration, attached by a peptide linkage to substituent B or a hydrophobic group attached to the nitrogen atom of substituent B; B is a residue of a hydrophobic α-amino acid or the L-configuration or a cyclic imino acid, which can bear one or more alkyl substituents attached to the ring, which substituents may bridge to form a cyclic structure; W is H or a lower alkyl, aryl or aralkyl substituent on the 3, 4, or 5 position of the piperidine or pyrrolidine ring; D is p-phenylmethyl, p-phenylethyl, ethylene, butylene, or propylene; Y is carbonyl; Z has a chain length between 12 and 40 and preferably 20 atoms; G and G' are the same or different and are Asp, Glu, ##STR42## wherein n is 1 or 2, X' is L-phe, L4FPhe or L-4ClPhe; Q is proline, pipecolic acid, sarcosine or Glu; W' is H or a lower alkyl, aryl or aralkyl substituent on the 3, 4 or 5 position of the piperidine or pyrrolidine ring; W' is H or a lower alkyl, aryl or aralkyl substituent on the 3, 4 or 5 position of the piperidine or pyrrolidine ring; ##STR43## J is H, OH, ##STR44## substituted in the para position and R' is a hydroxyl group or ##STR45## wherein R 2 and R 3 are straight chain or branched alkyl chains having 1 to 6 carbon atoms and may be joined to form a ring of 5-6 members.

Claim 41

A peptide according to claim 37, wherein X is D-Phe, D-4FPhe or D-4ClPhe wherein the α-amino group is neutralized by acetylation or benzoylation, or X is naphthalenesulfonyl, benzenesulfonyl, toluenesulfonyl; B is Val, pipecolic acid or Pro; W is hydrogen or a lower alkyl, aryl or aralkyl substituent on the 3,4 or 5 position of the piperidine or pyrrolidine ring; D is propylene of the ring when B is Pro or pipecolic acid or phenylmethyl; Y is carbonyl; Z is ##STR46## wherein n is an integer ranging from 1 to 4, the native hirudin48-54 sequence, or a synthetic spanner of the general formula ##STR47## wherein n is an integer ranging from 1 to 4; and L is a hexapeptide or saturated or unsaturated alkyl chain corresponding to 18 atoms or less of a hexapeptide; R is Glu-Glu-Tyr-Leu-Gln-OH, Leu-OH or Glu-Glu-Tyr-Leu-R' wherein R' is a hydroxyl group or a group having the following formula: ##STR48## wherein R 2 is --CH 3 or phenylethyl, R 3 is H or --CH 3 or R 2 and R 3 may be joined together to form --CH 2 --CH 2 --CH 2 --CH 2 --, --CH 2 --CH 2 --CH 2 --CH 2 --CH 2 -- or --CH 2 --CH 2 --O--CH 2 --CH 2 --.

Claim 42

A compound according to claim 3 selected from the group consisting of: P79 (SEQ ID NO:1) (BCH-1709): Ac(D-Phe)-Pro-Arg-(CH 2 ) 2 (CO)-QSHNDGDFEEIPEEYLQ-OH; P102 (SEQ ID NO:2): Ac(D-Phe)-Pro-Arg-(CH 2 ) 3 (CO)-QSHNDGDFEEIPEEYLQ-OH; P103 (SEQ ID NO:3): Ac(D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)-QSHNDGDFEEIPEEYLQ-OH; P109 (SEQ ID NO:4): Ac(D-Phe)-Pro-Arg-CH 2 (CO)-GSHNDGDFEEIPEEYLQ-OH; P183 (SEQ ID NO:5): Ac(D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--CH 2 --CH═CH--CH 2 --(CO)]-DFEPIPL-OH; P184 (SEQ ID NO:6) (BCH-1710): Ac(D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--CH 2 --CH═CH--CH 2 --(CO)] 2 -DFEPIPL-OH; P185 (SEQ ID NO:7): Ac(D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--CH 2 --CH═CH--CH 2 --(CO)] 3 -DFEPIPL-OH; P290 (SEQ ID NO:8) (BCH-1719): Ac(D-Phe)-thioPro-Arg-(CH 2 ) 2 (CO)-QSHNDGDFEEIPEEYLQ-OH; P311 (SEQ ID NO:9) (BCH-1721): Ac(D-Cha)-Pro-Arg-(CH 2 ) 2 (CO)-QSHNDGDFEEIPEEYLQ-OH; P314 (SEQ ID NO:10) (BCH-1726): Ac(D-Cha)-Pro-Arg-(CH 2 ) 2 (CO)-QSHNDGDFEPIPEEY-(Cha)-Q-OH; P536 (SEQ ID NO:11): (D-Cha)-Pro-Arg-CH 2 N(COCH 3 )CH 2 (CO)-(Gly) 4 -DYEPIPEEY-(Cha)-D-OH; P574 (SEQ ID NO:12): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-(Gly) 4 -DFEEIPEEYLQ-OH; P596 (SEQ ID NO:13) (BCH-2773): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-(GLY) 4 -DYEPIPEEACha-(D)Glu-OH; P597 (SEQ ID NO:14): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-(Gly) 4 -DFEEIPEEYLQ-OH; P603 (SEQ ID NO:15): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-Abu-Gly-DYEPIPEEA-(Cha)-)D-Glu)-OH; P604 (SEQ ID NO:16): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-Ava-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH; P605 (SEQ ID NO:17): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-Aca-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH; P606 (SEQ ID NO:18) (BCH-2774): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-Aha-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH; P609 (SEQ ID NO:19): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-(Gly) 4 -DYEPIPEEA-(Cha)-(D-Glu)-OH; P617 (SEQ ID NO:20) (BCH-2772): H-(D-Phe)-Pro-Arg-CH 2 SCH 2 (CO)-(Gly) 4 -DFEEPIEEYLQ-OH; P618 (SEQ ID NO:21): Ac(D-Phe)-Pro-Arg-CH 2 SCH 2 (CO)-(Gly) 4 -DFEEPIPEEYLQ-OH; P658 (SEQ ID NO:22): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-NH(CH 2 ) 2 CO-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH; P659 (SEQ ID NO:23): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-Gly-Gly-DYEPIPEEA-(Cha)-(D-Glu)-OH; P660 (SEQ ID NO:24): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-NH(CH 2 ) 3 CO-DYEPIPEEA-(Cha)-(D-Glu)-OH; P661 (SEQ ID NO:25): (D-Cha)-Pro-Arg-CH 2 (4-pyridylacetyl)-NH(CH 2 ) 2 CO-DYEPIPEEA-(Cha)-(D-Glu)-OH; BCH-2408 (SEQ ID NO:26): Ac(D-Phe)-Pro-Arg-(CH 2 ) 2 (CO)-QSHNDGDFEPIPEEY-(Cha)-Q-OH; BCH-2414 (SEQ ID NO:27): Ac(D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--CH 2 --CH═CH--CH 2 --(CO)] 2 -DEFPIPY-OH; BCH-2423 (SEQ ID NO:28): succinyl(D-Phe)-Pro-Arg-(CH 2 ) 2 (CO)-QSHNDGDFEEIPEEYLQ-OH; BCH-2739 (SEQ ID NO:29): AC(D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--(CH 2 ) 4 (CO)] 2 -DFEPIPL-OH; BCH-2757 (SEQ ID NO:30): alpha-N-(Ac)(D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--(CH 2 ) 4 (CO)]-NGDFEPIPL-TFA salt; BCH-2758 (SEQ ID NO:31): (D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--(CH 2 ) 4 (CO)] 2 -DF-(4-thiahomoGlu)-PIPL-TFA salt; BCH-2763 (SEQ ID NO:32): (D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--(CH 2 ) 4 (CO)] 2 -DFEPIPL-TFA salt; and BCH-2767 (SEQ ID NO:33): (D-Phe)-Pro-Arg-(CH 2 ) 4 (CO)--[NH--(CH 2 ) 4 (CO)] 2 -FEPIPL-TFA salt.

Claim 43

A thrombin inhibitor selected from the group consisting of: P536 (SEQ ID NO:11): (D-Cha)-Pro-Arg-CH 2 N(COCH 3 )CH 2 (CO)-(Gly) 4 -DYEPIPEEY-(Cha)-D-OH; P617 (SEQ ID NO:20) (BCH-2772): H-(D-Phe)-Pro-Arg-CH 2 SCH 2 (CO)-(Gly) 4 -DFEEPIEEYLQ-OH; and P618 (SEQ ID NO:21): Ac(D-Phe)-Pro-Arg-CH 2 SCH 2 (CO)-(Gly) 4 -DFEEPIPEEYLQ-OH.

Claim 44

A thrombin inhibitor selected from the group consisting of: P536 (SEQ ID NO:11): (D-Cha)-Pro-Arg-CH 2 N(COCH 3 )CH 2 (CO)-(Gly) 4 -DYEPIPEEY-(Cha)-D-OH; P617 (SEQ ID NO:20) (BCH-2772): H-(D-Phe)-Pro-Arg-CH 2 SCH 2 (CO)-(Gly) 4 -DFEEPIEEYLQ-OH; and P618 (SEQ ID NO:21): Ac(D-Phe)-Pro-Arg-CH 2 SCH 2 (CO)-(Gly) 4 -DFEEPIPEEYLQ-OH.

Claim 45

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

Claim 46

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

Claim 47

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

Claim 48

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

Claim 49

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

Claim 50

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

Claim 51

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

Claim 52

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

Claim 53

A thrombin inhibitor: BCH-2763 (SEQ ID NO:32): (D)Phe-Pro-Arg-(CH 2 ) 4 (CO)--[NH(CH 2 ) 4 CO] 2 -DFEPIPL-TFA salt.

Claim 54

A thrombin inhibitor: BCH-2763 (SEQ ID NO:32): (D)Phe-Pro-Arg-(CH 2 ) 4 (CO)--[NH(CH 2 ) 4 CO] 2 -DFEPIPL-TFA salt.

Claim 55

A pharmaceutical composition containing a compound according to claim 3 wherein said compound is present in admixture with a pharmaceutically acceptable carrier.

Claim 56

A pharmaceutical composition containing a compound according to claim 40 wherein said compound is present in admixture with a pharmaceutically acceptable carrier.

Claim 57

A pharmaceutical composition containing a compound according to claim 3 wherein said compound is present in admixture with another therapeutically active agent.

Claim 58

A pharmaceutical composition containing a compound according to claim 40 wherein said compound is present in admixture with another therapeutically active agent.

Claim 59

A method for the treatment or prevention of vascular diseases of a mammal, including human, comprising the administration of an effective amount of a compound according to claim 3.

Claim 60

A method for the treatment or prevention of vascular diseases of a mammal, including human, comprising the administration of an effective amount of a compound according to claim 40.