Imperial Chemical Industries Limited

Zeneca Limited

Astrazeneca Ab

David Timms

Roger Camble

Anthony J Wilkinson

Sheila Irene Hauck

Neil James Hales

Ronald Cotton

Kenneth Gregory Hull

George Byron Mullen

Oluyinka Morenike Green

Michael Brian Giles

John E Fitton

Haihong Ni

Heather Carr

Alexander Louis Breeze

Compounds of Formula (1) and their pharmaceutically acceptable salts are described: Formula (1) Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described. 

Pyrrol derivatives with antibacterial activity

The present invention provides a conjugate of a solution stable G-CSF derivative and a water soluble polymer which is an acid stable physiologically active substance derived from naturally occurring G-CSF.

Conjugate of a solution stable G-CSF derivative and a water-soluble

Ribotoxins, such as restrictocin, mitogillin and alpha-sarcin which do not contain a cysteine for linkage to antibodies for immunotoxin production need to be modified for such linkage without compromising biological activity. Protein analogues of such native ribotoxins are provided in which both the analogue and the native ribotoxin can cleave only a single phosphodiester bond of 28S rRNA in a 60S ribosomal subunit and in which the analogue comprises only one cysteine available from covalent linkage to a partner, such as an antibody, which cysteine is not present in the native ribotoxin. Especially preferred analogues are restrictocin Cys 13, Cys 82, Cys 106 and Cys 110 and restrictocin Cys 150-Gly151. Corresponding DNA sequences, vectors, host cells, immunotoxins and pharmaceutical compositions are also claimed.

Restrictocin-like ribotoxin analogues comprising only one cysteine

Derivatives of naturally occurring G-CSF having at least one of the biological properties of naturally occurring G-CSF, and a solution stability of at least 35% at 5 mg/ml are disclosed in which the derivative has at least Cys.sup.17 of the native sequence replaced by a Ser.sup.17 residue and Asp.sup.27 of the native sequence replaced by a Ser.sup.17 residue. Nucleotide sequences coding for part or all of the amino acid sequence of the derivatives of the invention may be incorporated into autonomously replicating plasmid or viral vectors employed to transform or transfect suitable procaryotic or eucaryotic host cells such as bacteria, yeast or vertebrate cells in culture.

Polypeptide derivatives of granulocyte colony stimulating factor

Pharmaceutical compositions for continuous release of a physiologically active substance in which the physiologically active substance comprises a polypeptide covalently conjugated to a water soluble polymer show particularly desirable release characteristics. Polypeptides for use in the pharmaceutical compositions include G-CSF and solution stable derivatives thereof, human calcitonin and interleukin-2. The material of the composition may be a polylactide or biodegradable hydrogel derived from an amphipathic block copolymer. The compositions enable a therapeutically effective polypeptide to be continuously released over a prolonged period of time following a single administration of the pharmaceutical composition to a patient.

Continuous release pharmaceutical compositions

Compounds of the formula: ##STR1## wherein R.sup.1 stands for an alk-2-enyl radical of not more than 5 carbon atoms or a furylmethyl radical, R.sup.2 stands for an alk-2-enyl or alkyl radical of not more than 5 carbon atoms or a furylmethyl radical, &gt;N--A, B, D, E and F stand for defined amino acid or aza-amino-acid residues, and in particular one or both of B and D stand(s) for an amino acid residue of the formula --NH.C(1-3C alkyl)(1-3C alkyl).CO-- or a similar residue, and X stands for --OR.sup.7 or --NR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8, which may be the same or different, stand for hydrogen or a (1-4C)alkyl radical, and wherein the linkages are all conventional peptide linkages or in the case of D-E the peptide linkage is replaced by the group --CH.sub.2 S--, and pharmaceutically-acceptable salts thereof. Processes for the manufacture of the compounds. Pharmaceutical compositions comprising one of the compounds and a pharmaceutically-acceptable diluent or carrier. The compounds are selective opiate .delta.-receptor antagonists.

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Macclesfield, United Kingdom

David Timms