Trigen Gmbh

Thrombosis Research Institute

Goran Karl Claeson

Vijay Vir Kakkar

John Joseph Deadman

Michael Finbarr Scully

Leifeng Cheng

Naoyashi Chino

Rainer Metternich

Said Mohamed Elgendy

Manfred Hans Philipp

Said Mohamed Anwar Elgendy

Manfred Hans Phillip

Manfred Hans Wilhelm Philipp

Peptides which act as inhibitors or substrates of thrombin are provided. The peptides of the invention have the general structural formula:

Inhibitors and substrates of thrombin

Pharmaceutical compositions comprising compounds of the formula:

Inhibitors of trypsin-like enzymes

Pharmaceutical compositions comprising compounds of the formula: ##STR1## in which X.dbd.H or is an N-protecting group; Y is 1-10 .alpha.-amino acids; Q1 and Q2 taken together represent the residue of a diol; R is C.sub.1-4, alkyl; and the asymmetric carbon atom marked * may have the D- or L-configuration, are useful in therapeutic methods of inhibiting thrombin.

This invention provides peptides of the formula ##STR1## wherein X is H, CH.sub.3 or an N-protecting group;

Pharmaceutical compositions comprising compounds of the formula: ##STR1## in which X.dbd.H or is an N-protecting group; Y is 1-10 .alpha.-amino acids; Q1 and Q2 taken together represent the residue or a diol; R is C.sub.1-4 alkyl; and the asymmetric carbon atom marked * may have the D- or L-configuration, are useful in therapeutic methods of inhibiting thrombin.

Peptides which act as inhibitors or substrates of thrombin are derived from the formula: D-Phe-Pro-Arg or its analogues, wherein Phe is substituted by (a), wherein Ar.sub.1 or Ar.sub.2 are the same or different and are selected from the group consisting of phenyl, thienyl, pyridyl, naphthyl, thionaphtyl, indolyl and saturated groups corresponding to these, optionally substituted by up to three groups selected from C.sub.1 -C.sub.3 alkyl and C.sub.1 -C.sub.3 alkoxy, L.sub.1 and L.sub.2 are the same of different and are selected from the group consisting of CH.sub.2, C.sub.2 --C.sub.2, O-CH.sub.2, S-CH.sub.2, Ar-L taken together optionally means H, diphenyl-methyl, fluorenyl or saturated groups corresponding to these, but one of the Ar-L cannot be H when the other [CH.sub.2 ].sub.n -Q, (c) where Q=H, amino, amidino, imidazole, guanidino or isothioureido and n=1-5, preferably 3-5, or C.sub.3 -C.sub.9 alkyl and C.sub.5 -C.sub.10 aryl or alkylaryl optionally substituted by up to three groups selected from hydroxy and C.sub.1 -C.sub.4 alkoxy; Z=CN, COR.sub.1, (d) or (e), where R.sub.1 =H, OH, CH.sub.2 Cl, CH.sub.2 --C.sub.2 --CO--pip, CF.sub.2 --CF.sub.2 --CO--pip, (f), (g), CH.sub.2 --C.sub.2 --CO--Pro--NHEt, CF.sub.2 --CF.sub.2 --CO--Pro--NHEt or a chromophoric group e.g. pHA, MCA, R.sub.2 and R.sub.3 are the same or different and are selected from the group consisting of OH, OR.sub.6 and NR.sub.6 R.sub.7, or R.sub.2 and R.sub.3 taken together represent the residue of a diol; where R.sub.6 and R.sub.7, which are the same or different, are C.sub.1 -C.sub.10 alkyl, phenyl or C.sub.6 -C.sub.10 arylalkyl, R.sub.4 and R.sub.5 are the same or different and are selected from R.sub.2, R.sub.3, Gly-pip, Ala-pip or Gly-Pro-NHEt.

Pharmaceutical compositions comprising compounds of the formula: ##STR1## in which X=H or is an N-protecting group; Y is Phe-Pro; Q1 and Q2 taken together represent the residue of a diol; R is C.sub.1-4 alkyl; and the asymmetric carbon atom marked * may have the D- or L- configuration, are useful in therapeutic methods of inhibiting thrombin.

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London, United Kingdom

Goran Karl Claeson