Ciba-geigy Corporation

Ucp Gen-pharma Ag

Novabiochem Ag

Peter Sieber

Bruno Kamber

Hans Rink

Bernhard Riniker

Werner Rittel

Hendrik M Greven

Max Brugger

Albert Hartmann

Hans Fritz

Manfred Liersch

Sefik Alkan

Francois Meyer

Robert Neher

Friedrich Werner Kahnt

Walter M&auml;rki

Ursula Seem&uuml;ller

Paul H Steenbergh

Cornelis J Lips

Hendrik S Jansz

Herbert Zuber

Beat Iselin

The invention relates to DNA sequences which code an eglin, expression plasmids containing such DNA sequences, hosts transformed with such expression plasmids, novel eglin compounds produced from such transformed hosts, monoclonal antibodies against eglins, hybridoma cells which produce such antibodies, and test kits for immunoassays containing such antibodies, and furthermore the processes for their preparation and a process for the preparation of eglins with the aid of the transformed hosts. The eglins which can be prepared according to the invention have useful pharmacological properties.

Process for preparing recombinant eglin, protease inhibitor

Compounds of the formula I, ##STR1## in which 'R.sub.1 is an amino protective group, and n stands for 1 or 2, R.sub.1 denotes hydrogen or an amino protective group, R.sub.2 denotes hydrogen or a carboxyl protective group and R.sub.3 denotes triphenylmethyl, 4-monomethoxy-trityl or 4,4'-dimethoxy-trityl, and reactive carboxylic acid derivatives of such compounds of the formula I in which R.sub.2 stands for hydrogen, are described. These compounds can be used as starting materials for the preparation of peptides. They are more suitable for this than are analogous compounds of the formula I in which R.sub.3 denotes hydrogen or one of the carbamoyl protective groups hitherto customary.

Protected amino acids and process for the preparation thereof

Described are peptides that have, as partial sequence of a larger peptide, or exclusively, the amino acid sequence of the formula I ##STR1## in which the cysteine residues can form intra- or inter-molecular disulphide bridges, and derivatives thereof having an amidated terminal carboxy group and/or an acylated terminal amino group, and their salts, DNA sequences that code for the mentioned peptides, micro-organisms that contain these DNA sequences, processes for the manufacture thereof, pharmaceutical preparations that contain the mentioned peptides in the form of their amides, and the use of these peptide-amides for the treatment of coronary circulation disorders and bone metabolism disorders.

Oligopeptides and intermediates and processes for their manufacture

Acylpeptides derived from somatostatin or from a derivative thereof having analogous action, in which the amino acids sequence is modified by omitting individual amino acids and/or by exchanging them for other amino acids, and in which the .epsilon.-amino group of the lysine residue in the 9-position, and optionally also the .epsilon.-amino group of the lysine residue in the 4-position and/or the N-terminal .alpha.-amino group carries the acyl radical of an optionally substituted alkanecarboxylic acid, and salts and complexes thereof can be used as antidiabetics and/or for combating gastrointestinal bleeding. They are manufactured by conventional methods of peptide chemistry.

Acylpeptides

Cyclic peptides of the formula ##STR1## in which trp represents L-Trp, D-Trp, or an analogous radical which carries a halogen atom in the indole nucleus, Ac.sub.A represents hydrogen, or an acyl radical Ac of a carboxylic acid present at the .epsilon.-amino group, A represents L-Phe, D-Phe, L-Phg or D-Phg, or a corresponding radical having a substituted or saturated phenyl ring, and B represents the residue of a .gamma.- or .delta.-amino-lower alkanecarboxylic acid which may carry an optionally substituted cyclic hydrocarbyl radical Ar, and also pharmacologically tolerable salts and therapeutically acceptable complexes thereof can be used as an antidiabetic in an analogous manner to somatostatin. They can be obtained by conventional processes of peptide chemistry, especially by cyclisation of corresponding linear peptides.

Cyclooctapeptides

The somatostatin-analogous cyclic octapeptides according to the invention of the general formula ##STR1## in which trp represents L-Trp or D-Trp, in which the benzene ring may be substituted by a halogen atom, and

Cyclopeptides and pharmaceutical preparations thereof and also processes

The somatostatin-analogous peptides according to the invention of the general formula ##STR1## in which Bmp represents the desaminocysteine radical

Peptides and processes for the manufacture thereof

Sulphur-free cyclopeptides with somatostatin-analogous aminoacid partial sequences, of the formula ##STR1## in which R is Asn, Ala or de-R, trp is D-Trp or L-Trp, which can be substituted in the benzene ring by halogen atoms or nitro groups, W is a free or etherified hydroxyl group or halogen atom present as a substituent on the benzene ring of the L-phenylalanine radical, or is hydrogen, X is the radical of an .omega.-amino-lower alkane-(mono or di)-carboxylic acid or de-X and Y is the radical of an .omega.-amino-lower alkane-(mono or di)-carboxylic acid or de-Y, and also acid addition salts and complexes thereof have biological properties similar to those of somatostatin and can be used, especially in the form of pharmaceutical preparations, for the treatment of excessive secretion of somatotropin, insulin and/or glucagon. The compounds according to the invention are obtained by cyclising a corresponding linear peptide compound in which the .epsilon.-amino group of the lysine radical and, if desired, also the hydroxyl group of the threonine radical are protected and detaching the protective groups which are present.

Novel cyclopeptides

The new hypocalcaemically active peptides of formula I ##STR1## and corresponding compounds in which one or more of the asparagine and glutamic acid radicals are replaced by the aspartic acid or glutamic acid radical and/or the aspartic acid radical is replaced by the asparagine radical, their dimers, especially those in which 2 identical peptide sequences (1-32 and 1'-32') are joined in an anti-parallel arrangement via the cysteine radicals 1,7' and 7,1' by means of a disulfide bond, and derivatives are useful as hypocalcaemic agents and are prepared by splitting off groups protecting at least one amino or one carboxyl group or oxidizing the corresponding sulfides to the disulfides or condensing together adequate peptides.

Peptides and process for their manufacture

Process for the manufacture of peptides which contain more than one disulphide bond characterized in that in one or two aminoacid sequences containing cysteine, in which disulphide bonds are to be produced, two cysteine radicals which are to be linked are protected by a mercapto-protective group R.sub.1 of the aralkyl type, two further cysteine radicals are protected by an acylaminomethyl group R.sub.2, the protective groups R.sub.1 are removed by treatment with iodine in the presence of a polyhalogenated lower aliphatic hydroxy compound or oxo compound, or a corresponding lower alkanoic acid lower alkyl ester, at the same time forming the disulphide bond between these cysteine radicals, which are protected by R.sub.1, and at any desired point after removal of the polyhalogenated compound the second disulphide bridge is formed in the usual manner.

Process for the manufacture of peptides containing cystine

Synthetic hypocalcaemic dotriacontapeptide of the formula

Hypocalcaemic peptides and processes for their manufacture

Temporary protection of amino groups by the group of the formula I ##EQU1## in which R.sub.1 represents lower alkyl, R.sub.2 lower alkyl or phenyl and R.sub.3 phenyl, and wherein the phenyl radicals are unsubstituted or substituted by lower alkyl, phenyl or lower alkylphenyl groups.

Process for the temporary protection of amino groups in peptide syntheses

The new hypocalcaemically active peptides of formula I

Growing community of inventors

Reinach, Switzerland

Peter Sieber