Patent GB-1462493-A (GB)
Title: Trypsin inhibitors and process for the production thereof
IPC: C07K14/00
Filed: 1974-09-06
Abstract: 1462493 Trypsin-callicrein inhibitor derivatives HOECHST AG 6 Sept 1974 [6 Sept 1973] 39110/74 Heading C3H A derivative of trypsin-callicrein inhibitor (TCI) in which each of the five free carboxyl groups in the inhibitor is bonded via a peptidic linkage to a residue of general formula wherein (i) x is zero; Y is a straight or branched chain alkyl radical having from 1 to 5 carbon atoms and which is substituted by a carboxyl group and W is hydroxyl or (ii) x is 1-10; Y is hydrogen or a straight or branched alkyl radical of 1-5 carbon atoms which may be substituted by carboxyl, hydroxyl or carbonamide groups and/or which together with the carbon atom to which it is bonded and together with the nitrogen atom adjacent to that carbon atom, may form a cycloaliphatic, nitrogen-containing ring, W is hydroxyl or, when two or more radicals Y contain a carboxyl group, W may represent NH 2 , NHCH 3 , NHC 2 H 5 , OCH 3 , OC 2 H 5 , may be prepared by (i) protection of the five primary amino groups of the trypsin-callicrein inhibitor easily removable by an acid, (ii) reaction with an amino acid or peptide of formula wherein Y is present as the t-butyl ester of any carboxyl group, W<SP>1</SP> is a tertiary butoxy group and, when 2 or more radical Y contain tertiary butyl groups, W<SP>1</SP> may be NH 2 , NHCH 3 , NHC 2 H 5 , OCH 3 , OC 2 H 5 , in the presence of 1- hydroxybenzotriazole and dicyclohexylcarbodiimide; (iii) deprotection of all protective groups with at least one acid. In the examples, the following peptides are prepared: penta(Glu-Glu-Glu-Glu-OH) -TCI, penta(Glu-Asp-Glu-Asp-OH)TCI, penta(Glu-Glu-Glu-OH)-TCI, penta(Glu-Glu-Asp-OH)-TCI, penta(Asp-Glu-Asp-OH)-TCI, penta(Asp-Ser-Asp-OH)-TCI, penta(Glu-Glu-D-Glu-OH)-TCI, penta(D-Glu-D-Glu-D-Glu-OH) -TCI, penta(Glu-Glu-OH)-TCI, penta(Glu-Asp-OH)-TCI, penta(Glu-D-Glu-OCH 3 )-TCI, penta(Asp-Glu-NH 2 )-TCI, penta(h-glutamic acid)-TCI, penta(h-aspartic acid)-TCI. The following intermediates are prepared: penta-BOC-TCI. TETRAPEPTIDES: Z and HCl.H - Glu- (Obu<SP>t</SP>) - Gtu(OBu<SP>t</SP>) - Glu(OBut) - Glu(OBu<SP>t</SP>)- OBu<SP>t</SP>; Z and HCl.H - Glu(OBu<SP>t</SP>) - Asp(OBu<SP>t</SP>)- Glu(OBu<SP>t</SP>)-Asp(OBu<SP>t</SP>)-OBu<SP>t</SP>. TRIPEPTIDES: Z and HCl.H-Glu(OBu<SP>t</SP>)- Glu(OBu<SP>t</SP>) - Glu(OBu<SP>t</SP>) - OBu<SP>t</SP>; Z and HCl.HGlu(OBu<SP>t</SP>) - Glu(OBu<SP>t</SP>) - Asp(OBu<SP>t</SP>) - OBu<SP>t</SP>; Z and HCl.HAsp(OBu<SP>t</SP>) -Glu(OBu<SP>t</SP>) -Asp(OBu<SP>t</SP>)- OBu<SP>t</SP>; HCl.H - D - Glu(OBut) - D - Glu(OBu<SP>t</SP>)- D - Glu(OBu<SP>t</SP>) - OBu<SP>t</SP>; Z and HCl.H - Glu- (OBu<SP>t</SP>) - Glu(OBu<SP>t</SP>) - D - Glu(OBu<SP>t</SP>)-OBu<SP>t</SP>. The dipeptide intermediates prepared are Z and HCl.H - Glu(OBu<SP>t</SP>) - Glu(OBu<SP>t</SP>) - OBu<SP>t</SP>; Z and HCl.H - Glu(OBut) - Asp(OBu<SP>t</SP>) - OBu<SP>t</SP>; Z and HCl.H - Glu(OBut) - D - Glu(OBu<SP>t</SP>)- OBu'. Pharmaceutical compositions, suitable for parenthal administration (especially infusion or intravenous injection), comprise the derivatives of callicrein-trypsin inhibitor in admixture with a pharmaceutically acceptable carrier.