Polymer-bound paclitaxel derivatives

• US 5,362,831 A
• Filed: 06/16/1993
• Issued: 11/08/1994
• Est. Priority Date: 06/19/1992
• Status: Expired due to Fees

• Current Assignee: Pharmacia & Upjohn LLC (Pfizer Inc.)
• Original Assignee: Farmindustria SA (Abbott Laboratories Incorporated)
• Inventors: Pesenti, Enrico, Angelucci, Francesco, Mongelli, Nicola, Suarato, Antonino, Biasoli, Giovanni
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Kulkosky, Peter F.
• Application Number:
  US08/077,065
• Time in Patent Office: 510 Days
• Field of Search: 424/486, 424/78.32, 424/78.08, 526/304, 526/307.4, 526/307.3
• US Class Current: 526/304
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems

Abstract

A polymer conjugate consisting essentially of: from 90 to 99.9 mol % of units represented by the formula ##STR1## from 0.1 to 5 mol % of units represented by the formula ##STR2## wherein one of R₁ and R₂ is a copolymer residue of the formula ##STR3## and the other one is hydrogen atom; from 0 to 9.9 mol % of units represented by the formula ##STR4## wherein R is a phenyl or t-butoxy group, R₃ is H or an acetyl group, A and A₁ which may be the same or different, represent a chemical single bond, an amino acid residue or peptide spacer selected from β Ala, Gly, Phe-Gly, Phe-Phe-, Leu-Gly, Val-Ala, Phe-Ala, Leu-Phe, Leu-Ala, Phe-Leu-Gly, Phe-Phe-Leu, Leu-Leu-Gly, Phe-Tyr-Ala, Phe-Gly-Phe, Phe-Phe-Gly, Phe-Leu-Gly-Phe, Gly-Phe-Leu-Gly-Phe,-βAla, Phe-Gly-βAla, Phe-Phe-βAla, Leu-Gly-βAla, Val-Ala-βAla, Phe-Ala-βAla, Leu-Phe-βAla, Leu-Gly-βAla, Phe-Leu-Gly-βAla, Phe-Phe-Leu βAla, Leu-Leu-Gly-βAla, Phe-Tyr-Ala-βAla, Phe-Gly-Phe-β, Phe-Phe-Gly βAla, Phe-Leu-Gly-Phe-βAla or Gly-Phe-Leu-Gly-Phe-βAla. The compounds are endowed with antitumor activity and show improved water solubility and decreased toxicity in comparison with paclitaxel or its known analogs. A method for their preparation and pharmaceutical compositions containing them are also described.

Claims

1. A polymer conjugate consisting essentially of:

from 90 to 99.9 mol % of units represented by the formula ##STR12## from 0.1 to 5 mol % of units represented by the formula ##STR13## wherein one of R₁ and R₂ is a copolymer residue of the formula ##STR14## and the other one is hydrogen atom;

from 0 to 9.9 mol % of units represented by the formula ##STR15## wherein R is a phenyl or t-butoxy group, the same or an acetyl group, A and A₁ which may be the same or different, represent a chemical single bond, an amino acid residue or peptide spacer selected from β

Ala, Gly, Phe-Gly, Phe-Phe-, Leu-Gly, Val-Ala, Phe-Ala, Leu-Phe, Leu-Ala, Phe-Leu-Gly, Phe-Phe-Leu, Leu-Leu-Gly, Phe-Tyr-Ala, Phe-Gly-Phe, Phe-Phe-Gly, Phe-Leu-Gly-Phe, Gly-Phe-Leu-Gly-Phe, Gly-β

Ala, Phe-Gly-β

Ala, Phe-Phe-β

Ala, Leu-Gly-β

Ala, Val-Ala-β

Ala, Phe-Ala-β

Ala, Leu-Phe-β

Ala, Leu-Gly-β

Ala, Phe-Leu-Gly-β

Ala, Phe-Phe-Leu β

Ala, Leu-Leu-Gly-β

Ala, Phe-Tyr-Ala-β

Ala, Phe-Gly-Phe-β

, Phe-Phe-Gly β

Ala, Phe-Leu-Gly-Phe-β

Ala or Gly-Phe-Leu-Gly-Phe-β

Ala.

2. A polymer conjugate according to claim 1, in which R represents a phenyl group, R₃ is an acetyl group and A is a Phe-Leu-Gly or Phe-Leu-Gly-β

Ala residue.

3. A polymer conjugate according claim 1 or 2, which is a copolymer of 1-methacryloylamino-2-hydroxypropane, (methacryloylglycyl-phenylalanylleucylglycyl)3'"'"'-amino-2-hydroxypropane and 2'"'"'-(methacryloylglycylphenylalanyl-leucylglycyl-β

alanyl) paclitaxel.