Polymer-bound camptothecin derivatives

Details Polymer-bound camptothecin derivatives Polymer-bound camptothecin derivatives

1995-06-08

1998-06-30

Knode, Marian C.

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

514283, 514 81, 546 23, 546 48, 4242801, C08F 2056, C08F12056, C08F22056, A01N 4342

Patent

active

057735220

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/03154 filed Sep. 21, 1994.
The present invention refers to water soluble polymer-bound camptothecin and polymer-bound camptothecin derivatives endowed with antitumour activity, to a process for their preparation and to pharmaceutical compositions containing them.
Camptothecin is an alkaloid isolated from the leaves and bark of Camptotheca acuminata; other analogs of camptothecin are also known and were prepared by semisynthesis from camptothecin or by total synthesis: see J.Amer.Chem.Soc. 94(10), 3631 (1972); J.Chem.Soc.D. (7), 404 (1970); U.S. Pat. No. 4,981,969 (Jan. 1, 1991); U.S. Pat. No. 5,049,668 (Sep.17, 1991).
Camptotnecin has a pentacyclic structure consisting of a fused ring system forming a quinoline ring (rings A and B), a pyrrolidine ring (ring C), a pyridone ring (ring D) and an .alpha.-hydroxy-.delta.-lactone moiety (ring E). Camptothecin and several of its A ring-substituted derivatives exhibit antitumour activity against a variety of solid tumour lines, including J.Clin.Pharmacol. 30, 770 (1990); Cancer Chemother.Pharmacol. 28, 192 (1991)!.
Camptothecin, as well as most of its derivatives, is practically insoluble in vehicles suitable for parenteral administration due to weak basicity of the quinone nitrogen atom. In order to solubilize camptothecins, several water soluble prodrugs have been proposed such as 20-O-phosphate or 20-O-acylamino derivatives which can be protonated by mineral acids, thus allowing solubility: see U.S. Pat. No. 4,943,579 (Jul. 24, 1990). Toxic side effects, including haematological and gastrointestinal ones, are associated with the administration of these drugs. Numerous attempts have been made to improve therapeutic index of camptothecin by modifying its structure.
The present invention provides polymeric conjugates of camptothecins which are water soluble and possess antitumor activity in vivo and decreased toxicity. More particularly, the invention provides a polymeric conjugate which is denoted herein as A and which consists essentially of: represented by formula 1: ##STR4## (ii) from 1 to 40 mol % of 20-O-(N-methacryloylglyl aminoacyl)camptothecin units represented by formula 2 ##STR5## carbonyl groups which are separated by at least three atoms and O-CPT represents a residue of a camptothecin, the C-20 group of the camptothecin (iii) from 0 to 10 mol % of N-methacryloylglycine or N-(2-hydroxy-propyl) methacryloylglycinamide units represented by formula 3: ##STR6## wherein Z represents hydroxy or a residue of formula --NH--CH.sub.2 --CH(OH)--CH.sub.3.
The invention also provides a process for preparing a polymeric conjugate as defined above, which process comprises reacting a 20-O-acylamino-camptothecin derivative of formula 7: essentially of: represented by formula 1: ##STR7## and (iv) from 40 to 1 mol % of N-methyacryloylglycine units represented by formula 4: ##STR8## wherein R.sub.2 is (a) the residue of an active ester or (b) hydroxy; and optionally displacing the remaining active ester groups with 1-amino-2-propanol.
The polymeric conjugate A contains the N-(2-hydroxypropyl) methacryloylamide units represented by the formula 1 in a proportion of 60 mol % or more, for example at least 80 mol % or at least 85 mol %. These units may be present in an amount from 91 to 98 mol %. The conjugate may also contain from 1 to 40 mol % of the 20-O-(N methacryloylglycyl-aminoacyl)camptothecin units represented by the formula 2, for example from 1 to 20 mol % of such units. The conjugate may contain from 1 to 8 mol %, for example from 2 to 6 mol %, of these units. nine, atoms long. Typically, the group is susceptible to intracellular hydrolysis. Preferably it is resistant to extracelluar hydrolysis. The spacer group may be a peptide spacer, for example from 1 to 4 or 2 to 4 amino acid residues long. The spacer may thus be a dipeptide, peptide or tetrapeptide. 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 and Phe-Leu-Gly-Phe. which Y is C.sub.3 -C.sub.6 lin

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