Patent ID: 6060451
Filing Date: 2000-05-09
Classification: A61K,A61P,C07K

Abstract:
A thrombin inhibitor of formula (I)AS--Y--Z--A (I)and pharmaceutically acceptable salts thereof whereinAS is a hydrophobic moiety which binds the catalytic site of thrombin, said hydrophobic moiety comprising (a) one or two hydrophobic .alpha.-amino acids, which are optionally substituted by a lower alkyl, aryl or aralkyl, and (b) a guanidino group;Y is (CO), --CH.sub.2 --, or --CH.sub.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; andA is an acidic portion of formula (III) ##STR30## wherein 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 an L-.alpha.-amino acid or a cyclic L-imino acid;Q.sup.1 and Q.sup.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.sup.1 or Q.sup.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 JGlu-Glu-Phe-Leu-Glx-R' JwhereinJ is H, OH, O--SO.sub.2 --OH, --CH.sub.2 --SO.sub.2 --OH or --O--PO.sub.2 --OH, or --CH.sub.2 --PO.sub.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.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 the group consisting of O, S and NHand 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.