Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for...
Patent
1993-01-07
1994-02-15
Wityshyn, Michael G.
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
435 681, 435181, 435189, 435832, 514 2, 530397, 530399, 424 8591, 424 944, C12N 900, C12P 2106, A01N 3718
Patent
active
052866378
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new biologically active drug polymer derivatives, namely, peptides or protein derivatives useful as medicaments. It relates more particularly to peptide or protein polyethylene glycol derivatives wherein the peptide or protein moeity is linked to the polyethylene glycol residue by means of an amino acid or peptide spacer arm.
Modification of biologically active substances such as peptides or proteins with monomethoxy polyethylene glycol is reported to change extensively their physical, chemical, enzymological, immunological, as well as their pharmacological and pharmacokinetic properties. Several methods to achieve such a modification have so far been reported (see e.g. U.S. Pat. Nos. 4,179,337 and 4,766,106; Appl. Biochem and Biotechnology, Vol. 11, p. 141/1985).
Such modified peptide or protein derivatives exhibit some advantages when compared to the peptide or protein itself: increased water solubility, decreased antigenicity or increased half-life of the circulating peptide or protein.
The use of such modified bioactive compounds, however, is not satisfying as the following drawbacks have been observed: difficulty to obtain a selective incorporation of a radioactive probe into the polymer drug adduct necessary for pharmacokinetic experiments; inactivation of some enzymes; difficulty to program (or to modulate) the cleavage of the polymer-protein bond by specific enzymes in the body; difficulty of introduction into the polymerdrugs adduct amino acid sequences which may confer targeting properties to the adducts itself. These disadvantages are related to the chemistry employed in the polymer activation and to its direct linkage to the drug.
It has been found that some, if not all of the above mentioned drawbacks can be eliminated or at least significantly reduced by making use of the new drug polymer derivatives of the invention which are represented by the generic formula a dipeptide or tripeptide residue, and peptide or protein or NH or NH.sub.2 -containing drug residue.
Preferred species of compounds of formula (I) are those wherein R represents a methyl group and wherein n is an integer comprised between 40 and 115, i.e. those of which the polyethylene moiety exhibits a molecular weight of about 1800 to 5500, for example of 1900 and 5000.
Also preferred are the compounds of formula (I) wherein symbol X when combined with the adjacent NH and CO groups represents an amino acid selected from glycine, phenylylanine, tryptophan and norleucine, or a dipeptide or tripeptide such as Gly-Gly, Arg-Arg, Phe-Arg, Gly-Gly-Arg, Gly-Gly-Phe or Gly-Leu-Gly-Leu.
Also preferred are the compounds of formula (I) wherein symbol Z, when combined with the adjacent NH group represents the residue of a biologically active peptide, protein or drug, selected from the following species: urokinase, e.g.; synthetic analogues of same, e.g.; (ara-C), acyclovir e.g.
Some but not all of the most interesting peptide derivatives of formula (I) are mentioned and characterized individually in the Examples.
Consequently, the invention relates to new biologically active peptide derivatives of formula (I) as defined above, as well as to a method for preparing same.
The invention also relates to pharmaceutical compositions which comprise at least one of the compounds of formula (I) as active ingredient. Further objects of the invention shall appear from the specification or the claims.
The method of the invention is based on the linkage of an amino acid or peptide spacer arm of various structures and properties to the hydroxyl function of monoalkoxypolyethylene glycol through a carbonate linkage which involves the NH.sub.2 group of the amino acid or peptide. This reaction is followed by the activation of the COOH function of the amino acid or peptide spacer arm as succinimidyl ester which, thus, becomes reactive towards the amino group of the biologically active peptide, protein or drug.
More specifically the method of the invention consists of: 2,4,5-trichlorphenylchloroformate or 4-nitrophenylchloroformate to obtai
REFERENCES:
patent: 4179337 (1979-12-01), Davis et al.
patent: 4766106 (1988-08-01), Katre et al.
patent: 4791192 (1988-12-01), Nakagawa et al.
patent: 4894443 (1990-01-01), Greenfield et al.
patent: 4935355 (1990-06-01), Ulmer et al.
patent: 5066591 (1991-11-01), Hallewell et al.
K. Ulbrich et al., Poly(ethylene glycols) Containing Enzymatically Degradable Bonds, Makromol. Chem. 187, 1131-1144 (1986.
F. Veronese, et al; "Applied Biochemistry & Biotechnology"; vol. (11), pp. 141-152; (1985) Surface Modification of Proteins (Activation of Monomethoxy-Polyethylene Glycols by Phenylchloroformates and Modification of Ribonuclease and Superoxide Dimutase).
Savoca et al; "Preparation of Non-Immunogenic Arginase by the Covalent Attachment of Polyethylene Glycol"; Biochimica et Biophysica Acta, 578 (1979)pp. 47-53.
Deghenghi Romano
Orsolini Piero
Sartore Luciana
Veronese Francesco
Debiopharm S.A.
Leary Louise N.
Wityshyn Michael G.
LandOfFree
Biologically active drug polymer derivatives and method for prep does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Biologically active drug polymer derivatives and method for prep, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Biologically active drug polymer derivatives and method for prep will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1206272