WO2001000240A2

WO2001000240A2 - Antitumor compound

Info

Publication number: WO2001000240A2
Application number: PCT/EP2000/005348
Authority: WO
Inventors: Antonino Suarato; Francesco Angelucci; Mariella Farao; Valeria Caiolfa
Original assignee: Pharmacia & Upjohn Spa
Priority date: 1999-06-29
Filing date: 2000-06-08
Publication date: 2001-01-04
Also published as: WO2001000240A3; AU5077500A; GB9915180D0

Abstract

The use of a compound of formula (1) in the preparation of a medicament for the treatment of pancreatic tumors.

Description

Antitumor Compound

The present invention relates in general to the field of cancer treatment and, more particularly, provides a soluble polymer-ca ptothecin conjugate in the treatment of pancreatic malignancies.

The present invention provides a pharmaceutical composition for use in pancreatic tumor therapy in mammals, including humans, comprising a compounds of formula 1

wherein: x represents the mole % of N- (2-hydroxypropyl) methacryloylamide and is from 85 to 97; y represents the mole % of 20-O- (N-methacryloyl-glycyl-aminoacyl-glycyl-) camptothecin and is from 3 to 15; z represents the mole ^r _c of N- (2-hydroxypropyl) methacryloyl glycinamide and is from 0 to 12 and a pharmaceutically acceptable carrier or excipient .

The polymer-bound conjugates of formula 1 were described and claimed in our international patent application EP98/06048, filed on September 22, 1998. The polymer-bound conjugates of formula 1 are random polymer, i.e. above formula does not indicate the exact monomer sequence, and have a molecular weight preferably in the range of from 10,000 to 45,000, more preferably from 18,000 to 35,000. We have now found that the conjugates of formula 1 are unexpectedly endowed with remarkable antitumor activity against pancreatic malignancies, which are known to be not sensitive to the other known anticancer agents. Preferably, the polymeric conjugates of the formula 1 contain the N- (2-hydroxypropyl) methacryloyl amide units in a proportion of 90 % or more; more preferably x is 90%. The conjugate also contains from 3 to 10 mol% of the units with the camptothecin residue, (y) , more preferably 10 mol c of such units. Preferably in the conjugate of formula (1) z is about 0. Content of active camptothecin in the conjugate of formula (1) may be from 2 to 15% (weight/weight) , more preferably 10% (w/w) .

More particularly, the present invention is directed to the compound of formula 1 having Mw of about 20,000; Mw/Mn of about 1.5 and content of camptothecin, determined after alkaline hydrolysis, of about 10% w/w.

A further aspect of the present invention is to provide a method of treating a mammal including humans, suffering from pancreatic tumor comprising administering to said mammal a therapeutically effective amount of a polymeric conjugate of the invention. The condition of the human patient can thus be improved.

The dosage range adopted will depend on the route of administration and on the age, weight and condition of the patient being treated. The polymeric conjugate of formula 1. can be typically administered by parenteral route, for example intramuscularly, intravenously or by bolus infusion. A suitable dose range is from 1 to 1000 mg of camptothecin equivalent per πr body surface area, for instance from 10 to 200 mg/m². The pharmaceutical compositions of the present invention containing the polymeric conjugate 1 may be formulated together with a pharmaceutically carrier or diluent. Typically they are formulated for parenteral administration, for example by dissolution in water for injection or physiological saline.

By the term * administered * or * administering" as used herein is meant parenteral and /or oral administration. By "parenteral" is meant intravenous, subcutaneus and intramuscolar administration.

In the method of the subject invention, for the administration of the the pharmaceutical compositions of the present invention the course of therapy generally employed is from about 1 to about 1000 mg/m² of captothecin of camptothecin equivalent per m² body surface area for one to about three days. More preferably, the course therapy employed is from about 100 to about 500 mg/nr of body surface area per day for one to five consecutive days. In a further aspect, the present invention is directed to the preparation of a pharmaceutical composition contaning an effective amount of a compound of formula 1 in the therapy of pancreatic tumor in mammals, including humans, as well as to the use of a compound of formula 1 for the treatment of pancreatic tumors. The following biological examples illustrate the invention. Antitumor Activity

Polymeric camptothecin conjugate 1 was tested on human pancreatic carcinoma (Capan 1) transplanted in nude mice, in comparison with the free camptothecin (Campto) by i.v. route. Compound 1 was found non toxic and gave >95% tumor inhibition at all tested doses with an exceptional high number of tumor free animals at the end of the experiment (90 days) , Table 1. Table 1: Antitumor Activity of 1 against human pancreatic carcinoma (Capan 1) in comparison with free camptothecin.

Tumor fragment were implanted sc. Treatment started when tumor was palpable.

TIo Inhibition of tumor growth 1 week after the last treatment .

Tox: Number mice died for toxicity/total number of mice Tumor-free: cured mice 90 days after tumor implant.

ΔTGD: Tumor growth delay of treated - Tumor growth delay of control animals.

Claims

1. Use of compound of formula 1

wherein: x represents the mole % of N- (2-hydroxypropyl) methacryloylamide and is from 85 to 97; y represents the mole % of 20-O- (N-methacryloyl-glycyl-aminoacyl-glycyl- ) camptothecin and is from 3 to 15; z represents the mole % of N- (2-hydroxypropyl) methacryloyl glycinamide and is from 0 to 12; in the preparation of a medicament for the treatment of pancreatic tumors.

2. Use according to claim 1 wherein x is from 90 to 97, y is from 3 to 10 and z is about 0.

3. Use according to claim 1 or 2 wherein the compound of formula (1) has a Mw of about 20,000, a value of Mw/Mn of about 1.5 and a content of camptothecin, determined after alkaline hydrolysis, of about 10 % w/w.