Ciba-geigy Corporation

Ucp Gen-pharma Ag

Novartis Corporation

Markus G Grutter

Manfred Liersch

Hans Rink

Bernd Meyhack

Sefik Alkan

Walter Marki

Francois Meyer

Albert Hinnen

Andreas Meister

Verena Steiner

Reinhard Maschler

Dirk Heinz

Robert Mah

Albert Schmitz

Nissim Claude Cohen

Jurgen Klaus Maibaum

Derek E Brundish

Vittorio Rasetti

John Peter Priestle

Heinrich Rueger

Fritz Raschdorf

The invention relates to DNA sequences that code for the amino acid sequence of the thrombin inhibitor hirudin, hybrid vectors containing such DNA sequences, host cells transformed with such hybrid vectors, novel polypeptides with thrombin-inhibiting activity produced from such transformed host cells, processes for the manufacture of these DNA sequences, hybrid vectors and transformed host cells, and processes for the manufacture of these thrombin-inhibitors using the transformed host cells. The hirudin compounds that can be produced according to the invention have valuable pharmacological properties.

Process for the manufacture of thrombin inhibitors

Compounds of the formula I ##STR1## in which R.sub.1 is arylamino, N-aryl-N-(lower alkoxy-lower alkyl)-amino, N-aryl-N-aryl-lower alkyl-amino or heterocyclyl bonded via a ring carbon atom, X is a carbonyl or methylene group, R.sub.2 and R.sub.3 independently of one another are hydrogen or lower alkyl or, together with the carbon atom with which they are bonded, are a cycloalkylidene radical, R.sub.4 is hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl, R.sub.5 is hydroxyl, lower alkanoyloxy or lower alkoxycarbonyloxy, R.sub.6 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkyl-lower alkyl, aryl-lower alkyl or heteroaryl-lower alkyl having 5 to 7 ring atoms in the heteroaryl ring and R.sub.7 is hydrogen or lower alkyl, or R.sub.6 and R.sub.7, together with the carbon atom with which they are bonded, are a cydoalkylidene radical and R.sub.8 denotes an aliphatic, cycloaliphatic-aliphatic or heteroarylaliphatic radical, and their salts can be used as active ingredients for medicaments for treatment of high blood pressure.

2,9-diamino- and 2-amino-8-carbamoyl-4-hydroxy-alkanoic acid amide

Peptide derivatives corresponding to the carboxy terminal sequence of

Novel polypeptides, designated hirullins, have a strong antithrombic activity and can therefore be used for the therapy and prophylaxis of thromboses. Said compounds are isolated from the leech Hirudinaria manillensis or are produced by conventional peptide synthesis or by recombinant DNA techniques. DNA sequences encoding hirullins P6 and P18 are supplied, hybrid vectors and transformed microorganisms for recombinant hirullin production are supplied.

DNA vector and recombinant host cell for production of hirullin P6 and

DNA encoding novel eglin mutants that differ from the natural eglins B and C by the replacement of amino acids in the region of the active center (amino acid 45) by other amino acids are provided. The mutants, which are produced by recombinant genetic engineering, have valuable pharmacological properties.

Genes encoding eglin C mutants

Novel polypeptides, designated hirullins, have a strong antithrombic activity and can therefore be used for the therapy and prophylaxis of thromboses. Said compounds are isolated from the leech Hirudinaria manillensis or are produced by conventional peptide synthesis or by recombinant DNA techniques.

Polypeptides with an anticoagulant activity

Novel elgin mutants that differ from the natural eglins B and C by the replacement of one, two or three amino acids in the region of the active center (amino acids 45 and 46, Leu-Asp) by other amino acids are provided. The mutants, which can be produced by recombinant genetic engineering, have valuable pharmacological properties.

Modified eglin proteins

Novel hybrid interferons are produced which are derived from lymphoblastoid interferons .alpha.-2 and .alpha.-3 belonging to the interferon .alpha.B and .alpha.D groups, respectively. The novel hybrid interferons possess valuable antiviral and antiproliferative properties.

Hybrid interferons

Growing community of inventors

Hochwald, Switzerland

Markus G Grutter