Biologically active drug polymer derivatives and method for preparing same

Claim 2

Biologically active drug polymer derivatives having the formula RO--(CH.sub.2 --CH.sub.2 O).sub.n --(CO)--NH--X--(CO)--NH--Z (I) wherein R represents a lower alkyl group, n is an integer between 25 and 250, X when combined with adjacent NH and CO groups represents an amino acid or a dipeptide or tripeptide residue, and Z when combined with the adjacent NH group represents a biologically active peptide or protein or NH or NH 2 containing drug residue.

Claim 3

Drug polymer derivatives according to claim 1 wherein R represents a methyl group, n is an integer between 40 and 115, X when combined with adjacent NH and CO groups represents an amino acid residue selected from the group consisting of glycine, phenylanaline, tryptophan and norleucine, or a dipeptide or tripeptide residue selected from Gly-Gly, Arg-Arg, Phe-Arg, Gly-Gly-Arg, Gly-Gly-Phe, and Gly-Leu-Gly-Leu, and Z when combined with the adjacent NH group represents the residue of a biologically active peptide, protein or drug selected from the group consisting of superoxidedismutase, ribonuclease, arginase, asparaginase, urokinase, ampicilline, doxorubicine, N-desmethyl-tamixofen, LHRH and synthetic analogues of same, somatostatin and synthetic analogues of same, calcitonin, interleukin-2, tumor necrosis factor, insulin, IGF-1, natural or recombinant interferon, adenin-arabinoside (ara-A), cytosin-arabinoside (ara-C) and acyclovir.

Claim 4

Method for preparing biologically active drug polymer derivatives having the formula (I) as defined in claim 1 which comprises: a) reacting a mono-alkoxy-polyethylene glycol derivative of formula RO--(CH.sub.2 --CH.sub.2 O).sub.n H (II) wherein R and n have the definition as indicated in claim 1 with 2,4,5-trichlorphenylchloroformate or 4-nitrophenylchloroformate to obtain the corresponding carbonate; b) reacting the carbonate thus obtained with an amino acid or a di- or tripeptide of formula H.sub.2 N--X--(CO)OH (III) wherein X is defined as indicated in claim 1 to obtain a compound of formula RO--(CH.sub.2 --CH.sub.2 O).sub.n --(CO)--NH--X--(CO)OH (IV) such that the carbonate is bonded directly to the amino group (--NH 2 ) of the amino acid or peptide; c) converting the compound of formula (IV) thus obtained into the corresponding succinimidyl ester; and d) finally, reacting the said succinimidyl ester with a biologically active peptide or protein or NH or NH 2 -containing drug of formula R--NH--Z or H2N--Z (V) wherein R and Z are defined as indicated in claim 1 such that the peptide, protein or drug is bonded to the activated carboxyl function of the ester.

Claim 5

Pharmaceutical composition which comprises as an active ingredient at least one biologically active drug polymer derivative of formula (I) as defined in claim 1; and a pharmaceutically acceptable carrier.

Claim 6

Pharmaceutical composition according to claim 4 which comprises as active ingredient a biologically active drug polymer derivative of formula (I) wherein R represents a methyl group, n represents an integer between 40 and 115, X when combined with adjacent NH and CO groups represents an amino acid residue selected from the group consisting of glycine, phenylanaline, tryptophan and norleucine, a dipeptide or tripeptide residue selected from Gly-Gly, Arg-Arg, Phe-Arg, Gly-Gly-Arg Gly-Gly-Phe and Gly-Leu-Gly-Leu, and Z when combined with the adjacent NH group represents a biologically active peptide, protein or drug residue selected from the group consisting of superoxidedismutase, ribonuclease, arginase, asparaginase, urokinase, ampicilline, doxorubicine, N-desmethyl-tamoxifen, LHRH and synthetic analogues of same, somatostatin and synthetic analogues of same, calcitonin, interleukin-2, tumor necrosis factor, insulin, IGF-1 natural or recombinant interferon, adenin-arabinoside (ara-A), cytosin-arabinoside (ara-C) and acyclovir.

Claim 7

Pharmaceutical composition according to claim 5 which comprises as active ingredient a biologically active drug polymer derivative selected from the group consisting of M-PEG 5000-Gly-superoxidedismutase, M-PEG 5000-Trp-superoxidedismutase, M-PEG 5000-nor-Leu-superoxidedismutase M-PEG 1900-Gly-superoxidedismutase, M-PEG 5000-Gly-arginase, M-PEG 5000-Gly-ribonuclease, M-PEG 5000-Gly-urokinase, M-PEG 5000-Gly-ampicillin, and M-PEG 5000-Gly-doxorubicin wherein M-PEG represents monomethoxy-polyethylene.