Trigen Gmbh

Thrombosis Research Institute

John Joseph Deadman

Vijay Vir Kakkar

Goran Karl Claeson

Michael Finbarr Scully

Said Mohamed Elgendy

Naoyashi Chino

Leifeng Cheng

Geeta Patel

Sophie Marie Combe-Marzelle

Sanjay Kumar Kakkar

Anthony James Kennedy

Mark Dolman

David John Madge

Michael Finbar Scully

Oliver Vimpany Arnold Boucher

Christopher Andrew Goodwin

Donovan St Green

Goran K Claeson

David Jonathan Madge

Jehan A Baban

Said Mohamed Anwar Elgendy

Donovan S Green

Suresh Babubhai Chahwala

Said Mohammed Elgendy

Salts of a peptide boronic acid drug, for example of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH). The counter-ion to the boronate may be an alkali metal or derived from a strongly basic organic nitrogen-containing compound.

Boronic acid salts useful in parenteral formulations

Salts of a pharmaceutically acceptable divalent metal and an organoboronic acid drug. Examples of such metals are calcium, magnesium and zinc. The organoboronic acid drug may be a boropeptide protease inhibitor. The salts may be formulated in oral dosage form.

Multivalent metal salts of boronic acids

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

Serine protease inhibitors

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

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.

Stable .alpha.-substituted boronic esters, e.g. for use in peptide synthesis, are prepared by reacting a substituted alkene of the formula: ##STR1## with a disubstituted borane of the formula: ##STR2## wherein: (i) R.sup.1 and R.sup.2 are each selected from various groups which are preferably not leaving groups;

Boric ester synthesis

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Melbourne, Australia

John Joseph Deadman