Biologically active drug polymer derivatives and method for preparing same

• US 5,286,637 A
• Filed: 01/07/1993
• Issued: 02/15/1994
• Est. Priority Date: 08/07/1989
• Status: Expired due to Fees

• Current Assignee: Debio Recherche Pharmaceutique SA
• Original Assignee: Debiopharm SA (Debiopharm)
• Inventors: Sartore, Luciana, Deghenghi, Romano, Veronese, Francesco, Orsolini, Piero
• Primary Examiner(s): Wityshyn, Michael G.
• Assistant Examiner(s): Leary, Louise N.
• Application Number:
  US08/001,434
• Time in Patent Office: 404 Days
• Field of Search: 435/183, 435/832, 435/189, 435/69, 435/181, 424/85.91, 424/94.4, 514/2, 530/397, 530/399
• US Class Current: 435/183
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: Y10S 435/832 Bacillus

Abstract

New biologically active drug polymer derivatives, namely peptides or protein derivatives, are useful medicaments and are represented by the generic 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 comprised 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 NH₂ containing drug residue.

Claims

1. Biologically active drug polymer derivatives having the formula

View Dependent Claims (2, 3, 4, 5, 6)

2. 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.

3. 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

space="preserve" listing-type="equation">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

space="preserve" listing-type="equation">H.sub.2 N--X--(CO)OH (III)

wherein X is defined as indicated in claim 1 to obtain a compound of formula

space="preserve" listing-type="equation">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 (--NH₂) 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 NH₂ -containing drug of formula

space="preserve" listing-type="equation">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.

4. 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.

5. 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.

6. 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.