GB1569962A - Anti-tumoral agents and their use - Google Patents

Abstract

The composition contains at least one water-soluble homopolymer or copolymer which contains unsaturated mono- or polyhydroxy compounds or their esters or urethanes in incorporated form. The composition is prepared by dissolving the homopolymers or copolymers in a physiological saline solution. For the treatment of tumours, the composition is administered intraperitoneally, intravenously or intramuscularly.

Description

ERRATUM Slip No. 2 SPECIFICATION NO 1569962 Page 15 headed Experimental Section, Column 2, first formula CH-NH2 for H2 C = C i CHZO-O-CO-NH2 CH20-CO-NH2 read H2C=C i CH20-CO-NH2 Page 30 line 44, before radical delete Artwork supplied THE PATENT OFFICE brune 1981 found in therapeuLu : cAinii.. .. - of the N-puryl- (or pyrimidyl)-N-puryl-pyrimidyl-ethylenediamine type tne auumma introduction oi i-aeoxy-rmose--nuoropynmiame mto cne moiecue increasmg tne action.

From all this work it can be seen that the antitumoral action of the polymers hitherto investigated on the experimental tumours used is frequently only at the lower limit of significance and in many cases is restricted only to prophylactic or adjuvantive effects. It should also be noted that the above mentioned prior investigations were in many cases carried out on allogenic murine tumours which tend towards spontaneous regression anyway and were not carried out systematically and under experimental conditions simi (54) ANTI-TUMORAL AGENTS AND THEIR USE (71) We, BAYER AKTIENGESELLSCHAFT, a body corporate organised under the laws of Germany of Leverkusen, Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to the use as antitumoral agents of certain known water-soluble homopolymers and copolymers.

It has already been disclosed that copolymeric, complex Cul'and Co'l salts of ethylenemaleic acid are active against Walker sarcoma [J. Med. Chem. 12 (1969), 1,180].

Polyoxyethylene sorbitane monooleate (Tween 80) has already been used for immunisation against the hyperdiploid Ehrlich tumour [Experientia 29 1973), 710].

Furthermore, various types of polycations, for example polyamidoamines, poly-N- morphinoethylacrylamide and N-oxide polymers have been tested for inhibition of the formation of metastases, with the findmg that only the dissemination of tumour cells could be influenced, and not the growth of metastases in situ or lymph node metastases [J. Med. Chem. 16 (1973) 496].

Furthermore, the activity of polymers with carboxyl groups against Sarcoma 180 as a function of the molecular weight, the charge density and the metal-binding capacity of the polycarboxyl groups has been described [Dissertation Abstr. Intern. B 33 (1973), 5,745].

Polyanions, for example poly-ammonium acrylate, acrylic acid acrylamide and copolymers of ethylene/maleic anhydride are supposed to have, in connection with their antitumoral action, a heparin-like effect and also a virus inhibition effect, and in addition to increase the immune responses [J. Med. Chem. 17 (1974), 1,335].

Other authors have examined the prevention of the cytotoxicity of quartz on cultures of macrophages [Brit. J. Pharmacol. 38, (1970)], differences in action between sterically different forms of the molecule resulting, depending on the experimental arrangement.

A condensation product of poly-oxypropylene and poly-oxyethylene (Pluronic F 68) has proved active against the formation of metastases of Walker 256 Ascites tumour, probably by influencing blood clotting capacity (Cancer 29 (1972), 171].

A 25% lengthening of the survival period of mice carrying tumours has also been found in therapeutic experiments on Sarcoma 180 using polymeric pyrimidine compound of the N-puryl- (or pyrimidyl)-N-puryl-pyrimidyl-ethylenediamine type the additional introduction of 1-deoxy-ribose-5-fluoropyrimidine into the molecule increasing the action.

From all this work it can be seen that the antitumoral action of the polymers hitherto investigated on the experimental tumours used is frequently only at the lower limit of significance and in many cases is restricted only to prophylactic or adjuvantive effects. It should also be noted that the above mentioned prior investigations were in many cases carried out on allogenic murine tumours which tend towards spontaneous regression anyway and were not carried out systematically and under experimental conditions simi lar to clinical conditions. In most cases data on the toxicity of the formulations are lack ing, despite the fact that incomplete excretion and storage in tissues can be expected from the application of high dosages of substances with molecular weights of over It has now been found that water-soluble homopolymers or copolymers which are built up, at least in part, from unsaturated monohydroxy or polyhydroxy compounds or their derivatives, such as esters or urethanes, including 1, 3-dihydroxy-2- methylenepropane and/or its derivatives (as disclosed in German published patent specification No. 2332562) have powerful antitumoral properties.

Surprisingly, in the molecular weight range from 1,000 to 50,000 these substances exhibit significant curative activity on solid tumours of syngenetic systems over a wide dosage range of from 0.5 to 500 mg/kg, preferably 5 to 250 mg/kg, under experimental conditions and methods of administration which are similar to clinical conditions. The therapeutic range of action of the substances thus proves to be unusually broad (LD 50, intravenously: 5,000 mg/kg, therapeutic dose: 0.5 to 500 mg/kg).

The agents according to the invention thus represent an important enrichment of pharmacy.

The present invention provides a pharmaceutical composition containing as an active ingredient a compound which is a water-soluble homopolymer or copolymer which polymer incorporates radicals of one or more, respectively, unsaturated monohydroxy and/or polyhydroxy compounds and/or derivatives thereof wherein the water-soluble polymer has a repeating unit of the general formula:

In these formulae:

R'is alkyl, cycloalkyl or aryl, R"is hydrogen, alkyl, cycloalkyl or aryl, A is hydrogen or methyl, B is hydrogen or methyl, Y and Z are the same or different and each is a radical of a monomer which can be copolymerised with an unsaturated monohydroxy or polyhydroxy compound or derivative thereof, said monomer (s) being such that the resulting homopolymer or copolymer is substantially water-soluble, p denotes from 30 to 100 mol %, q denotes from 0 to 70 mol %, and r denotes from 0 to 70 moI %, or where Y and/or Z includes a carboxylic acid group, a pharmaceutically acceptable salt thereof, in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent.

The invention provides in one aspect a composition according to the invention wherein the water-soluble homopolymer or copolymer contains radicals of 1,3dihydroxy-2-methylenepropane and/or derivatives thereof.

Copolymerisable monomers providing Y and z. which can be used to make the com pounds of formulae I to IV are, for example : maleic acid, maleic anhydride, fumaric acid, acrylic acid, optionally in the form of a salt, acrylamide, fumaric or maleic acid half-amides, optionally in the form of a salt, styrene, hydroxyalkyl acrylate and methacrylate, sulphoalkyl acrylate and methacrylate, vinylpyrrolidone, vinylcaprolactam, vinyl- pyridine, vinylimldazole, allylhydantoin or salicylic acid ~ ~ The proportions ot the moivictual comonomers trom which the copolymers which can be used according to the invention are built up can be varied within wide limits. However the composition must be chosen so that a water-soluble copolymer is formed.

Examples of homopolymers or copolymers or repeating units thereof, to be used according to the invention, which contain unsaturated monohydroxy or polyhydroxy, radicals and, or their derivatives are the following:

The unsaturated monohydroxy and polyhydroxy compounds used in the polymers according to the invention are known. From these substances, by known processes, numerous derivatives such as esters can be prepared by esterification and the corresponding urethanes can be prepared by reaction with isocyanates.

The homopolymers and copolymers may be prepared from the monomers by free radical polymerisation with the aid of peroxides, for example benzoyl peroxide, di-tert.butyl peroxide, dilauroyl peroxide, dicumyl peroxide, tert.-butyl hydroperoxide, cumene hydroperoxide or diacetyl peroxide, percarboxylic acid esters (for example tert.butylperacetate, perbenzoate, peroctoate, perpivalate or perisobutyrate), percarbonates (for example isopropyl peroxide-dicarbonate or ethylhexylpercarbonate), arylsulphonyl peroxides (for example acetylcyclohexanesulphonyl peroxide) or azo compounds (for example asodiisobutyronitrile). In principle, all the customary polymerisation techniques can be used though bulk polymerisation, solution polymerisation and precipitation polymerisation are preferred. Homopolymers, in particular, are conveniently obtained by polymerisation in bulk; solution polymerisation and precipitation polymerisation are preferred in the case of copolymers and terpolymers.

Some unsaturated hydroxy compounds, however, cannot themselves be homopolymerised or copolymerised. Homopolymers or copolymers which are to contain free hydroxyl groups can nevertheless be prepared by homopolymerising or copolymerising the corresponding esters and subsequently carrying out saponification of the ester groups on the polymers to hydroxyl groups, preferably by Zemplen's method.

The compounds of the invention which are acids or bases and their pharmaceutically acceptable salts can be inter-converted in any suitable manner; methods for such interconversion are known in the art. Particularly preferred salts of polymers, of the invention which contain carboxylic acid groups are the sodium salts.

The compounds according to the invention have a powerful antitumoral action against animal and human tumours, coupled with extremely low toxicity, and are therefore useful in combating diseases caused by tumours.

As stated above, the invention also relates to the use in veterinary medicine of the polymeric active ingredients of the invention.

The present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.

The invention further provides a pharmaceutical composition containing a polymeric active ingredient of the invention in the form of a sterile and/or isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprising a polymeric active ingredient of the invention.

The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a polymeric active ingredient of the invention.

"Medicament"as used in this specification means phvsically discrete coherent portions suitable for medical administration."hledicament in dosage unit form"as used in this specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or sub-multipte (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclose within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third, or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.

The pharmaceutical compositions according to the invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders.

The diluents to be used in pharmaceutical compositions (e. g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following: (a) fillers and extenders, e. g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e. g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone ; (c) moisturizing agents, e. g. glycerol ; (d) disintegrating agents, e. g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e. g. paraffin; (f) resorption accelerators, e. g. quaternary ammonium compounds; (g) surface active agents, e. g. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e. g. kaolin and bentonite ; (i) lubricants, e. g. talc, calcium and magnesium stearate and solid polyethylene glycols.

The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.

The ingredient can also be made up in microencapsulated form together with one or several of the above mentioned diluents.

The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and fats (e. g. cocoa oil and high esters [e. g. C"-alcohol with C, 6-fatty acid]) or mixtures of these diluents.

The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e. g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e. g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e. g. chlorofluorohydrocarbons.

The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers ; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils [for example ground nut oil], glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.

For parenteral administration solutions and emulsions should be sterile, and, if appropriate, blood-isotonic. Preferably the solutions contain from 0.05 to 1 % w/v of the active ingredient. Conveniently the solutions are made up by dissolving the active compounds in physiological saline (0.9 % w/w aqueous sodium chloride).

The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e. g. water, ethyl alcohol, propylene glycol, surface-active agents (e. g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.

All the pharmaceutical compositions according to the invention can also contain col ouring agents and preservatives as well as perfumes and flavouring additions (e. g. peppermint oil and eucalyptus oil) and sweetemng agents (e. g. saccharin).

The pharmaceutical compositions according to the invention generally contain from 0.1 to 99.5, usually from 0.5 to 95% of the active ingredient by weight of the total composition.

In addition to a compound of the invention, the pharmaceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.

Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.

Such medicaments may include solvents of molecular weight less than 200 as sole diluent.

The discrete coherent portions constituting the medicament according to the invention will generally be adapted, by virtue of their shape or packaging, for medical administration and may be, for example, any of the following: tablets, (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.

The preferred daily dose for administration of the medicaments of the invention is from 25 mg to 25 g of active ingredient.

The production of the above mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient (s) with the diluent (s) to form a pharmaceutical composition (e. g. a granulate) and then forming the composition into the medicament (e. tablets).

This invention further provides a method of combating (including prevention, relief and cure of) the above mentioned diseases in non-human animals, which comprises administering to the animals a compound of the invention along or in admixture with a diluent or in the form of a medicament according to the invention.

It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally, subcutaneously or intravenously), rectally or locally, preferably intramuscularly, intraperitoneally or intravenously. Prefer red pharmaceutical compositions and medicaments are therefore those adapted for parenteral administration, such as sterile and isotonic solutions, especially in physiologi cal saline, and ampoules thereof. Administration in the method of the invention is preferably intraperitoneally, intravenously or intramuscularly.

In general it has proved advantageous to administer amounts of from 0.5 mg to 500 mg/kg of body weight, preferably from 5 to 250 mg/kg of body weight, per day to achieve effective results. Nevertheless, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subject to the treatment, the type of formulation in which the active ingredient is administered and the mode in which the administration is carried out, and the point in the progress of the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the above mentioned minimum dosage rate, whilst other cases the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day.

The substances listed in Table 2 were tested, for the induction of anti-tumoral action, in numerous experiments and under various test conditions on murine sarcoma 180, and some of them were also additionally tested on murine fibrosarcoma MCS 4 (Table 1).

The experimental procedures (a) and (b) below describe the methods of the investiga tions on these two experimental tumours. From the data given in these for the evalua tion of the experiment it can be seen that tumour weight indices 60. 5 are to be regarded as indicating significant or good activity.

Experimenta ! description (a) TUMOUR TESTS ON SARCOMA MCS 4 ON C57Bl MICE Species of animal: C57B1 mice Procedure: Maintenance of the strain : Subcutaneous or intramuscular innoculation of C57B1 mice weighing 20-22 g with a tumour suspension of MCS4 in 0.5 mi of 0.9% w/v strength NaCI solution 10-14 days after the last transplant.

Preparation of immunological screening tests : Subcutaneous innoculation of C57B1 mice weighing 20 g with 8 x 105 tumour cells in 0.5 ml of 0.9% w/v strength NaCl solution 10-14 days after the last transplant.

Treatment : Intraperitoneal, subcutaneous, intramuscular or intravenous injection of the required formulation solution once 7 days before or 7 days after the tumour transplant.

Duration of the experiment : 4 weeks from the tumour transplant. The animals are then killed and the tumours dissected.

Evaluation parameter : Inhibition of the growth of the tumours. This is determined quantitatively by calculating a tumour weight index (TW index) according to the formula 0 weight of tumours in the group of treated animals TW index = 0 weight of tumours in the control group Assessment of the results : TW index 1.0-0.8 = no action; 0.7-0.6 = trace of action; 0.5-0.4 = significant action; 0.3-0.2 = good action; and 0.1-0.0 = very good action.

Absence of recidivity at the end of the experiment = cure.

Assessment of side effects : Determination of the animal losses, assessment of the gen eral condition of the experimental animals, determination of the change in body weight, recording of the number of leucocytes in peripheral blood and a search for macroscopic changes in the organs are carried out in the course of the experiment.

Experimental description (b) TUMOUR TESTS ON SARCOMA 180 ON SWISS MICE Species of animal: Swiss mice Procedure: Maintenance of the strain : Intraperitoneal innoculation of Swiss mice (colony breeding) weighing 20-22 g with 1 x 106 Ascites cells of Sarcoma 180 in 0.5 ml of 0.9% w/v strength NaCI solution on the 7th day after the last transplant.

Preparation of screening tests : The same procedure as keeping of the strain, but sub cutaneous tumour cell innoculation of 5 x 105 Ascites cells in 0.3 ml of solution.

Treatment ; Intraperitoneal, subcutaneous, intramuscular or intravenous injection of the required formulation solutions once in all, either on the 7th day before the tumour transplant or on the 7th day after the tumour transplant.

Duration of the experiment : 28 days. The animals are then killed and the tumours dis sected.

Evaluation parameter : Inhibition of the growth of tumours. Determined quantitatively by calculating the tumour weight indes (TW index) according to the formula 0 weight of tumours in the group of treated animals TW index = 0 weight of tumours in the control group Assessment of the test results ; TW index 1.0-0.8 = no action; 0.7-0.6 = trace of action; 0.5-0.4 = significant action; 0.3-0.2 = good action; 0.1-0.0 = very good action.

Absence of recidivity after 3 months = permanent cure.

Assessment of the side effects : Determination of the animal losses, assessment of the general condition of the experimental animals, determination of the changes in body weight, recording of the numbers of leucocytes in peripheral blood and a search for macroscopic changes in the organs are carried out in the course of the experiment.

It can be seen from the test results (tumour weight (TW) index) with the formulations listed in Table 1 that the agents are able to induce significant tumour-inhibiting actions on Sarcoma 180, and also some of the agents on Fibrosarcoma MCS 4, using various dosages and methods of administration as well as different treatment days.

Table 1 Sarcoma 180 Fibrosarcoma MCS 4 Com- does administration treatment @umour dose administration treatment tumour pound mg/kg day* weight mg/kg day* weight 1 x index 1 x index # I 250 intraperitoneally -7 0.1 25 intraperitoneally -6 0.5 100 intramuscularly -7 0.2 50 intramuscularly -4 0.4 II 5 intraperitoneally +7 0.3 10 intraperitoneally -6 0.6 10 intramuscularly +7 0.4 50 intramuscularly +6 0.7 III 10 intraperitoneally +7 0.2 100 intraperitoneally +6 0.5 10 intramuscularly -7 0.2 100 intramuscularly +6 0.6 IV 250 intraperitoneally +7 0.3 - - - 250 intramuscularly +7 0.6 - - - V 10 intraperitoneally +7 0.2 - - - 10 intramuscularly +7 0.3 - - - VI 50 intraperitoneally -7 0.4 250 intraperitoneally -7 0.5 50 intramuscularly +7 0.3 10 intramuscularly -6 0.6 VII 25 intraperitoneally -3 0.3 50 intraperitoneally ** 7 0.4 25 intramuscularly +3 0.2 - - - VIII 100 intraperitoneally +7 0.1 100 intraperitoneally +10 0.2 25 intramuscularly +7 0.2 25 intramuscularly +6 0.2 IX 1 intravenously -7 0.2 0.05 intravenously -3 0.46 1 intravenously +7 0.3 0.25 intravenously -3 0.52 X 1 intravenously -7 0.36 0.05 intravenously +2 0.54 5 intravenously +7 1.09 10 intraperitoneally -7 0.49 XI 10 intraperitoneally -4 0.5 25 intraperitoneally -4 0.41 25 intraperitoneally +3 0.6 50 intraperitoneally +3 0.55 * Day -7 = 7 days before the tumor transplant Day + 7 = 7 days after the tumour transplant The structural formulae of the corresponding repeating units I"to XI"of the compounds I toXI given in Table 1 can be seen from Table 2 which follows.

TABLE 2

Experimental Section

Yield, Melting 1) Monomers % point : C 1,3bis- (amino-carboxy)-2-methylene-propane CH20-CO-NH2 H2C=C 63.2 178-179 CH2O-O-CO-NH2 1,3bis- (methylamino-carboxy)-2-methylene-propane CH20-CO-NH-CH3 H2C=C 97 84-86 CH2O-CO-NH-CH3 1,3bis-(iso-propylamino-carboxy)-2-methylene-propane CH2O-CO-NH-CH (CH3) 2 H2C = C 87 104-105 i CH20-CO-NH-CH (CH3) 2 1,3bis-(propylamino-carboxy)-2-methylene-propane CH2O-CO-NH-CH2CH2CH3 I H2C = C 99 83 1 CHzO-CO-NH-CH2CH2CH3 1,3 bis-(butylamino-carboxy)-2-methylene-propane CH20-CO-NH (CH2) 3CH3 H2C = C 86 55-56 CH20-CO-NH(CH2) 3CH3

Yield,Melting % point C 1,3-bis- (cyclohexylamino-carboxy)-2-methylene-propane 89 161-162 CO-03-'-'-'-'7 1,3-bis- (phenylamino-carboxy)-2-methylene-propane ^ CrfO-CX-nnr- ( ()) 94 129-130 C-03--/Q\ \ : J 1,3-diacetoxy-2-methylene-propane Ca2o-co-ca boiling point ca2 82 96-98 C CH2 O-CO-CE 1, 3-dipropioxy-2-methylene-propane CH20-CO-CH2-CH3 n H2C-C, 50 CH20-CO-CH2-CH,1.440 1,3-dibenzoxy-2-methylene-propane ~ nD 70 ozo-acx1.5521

% Melting nD Yield C 3-aminocarboxy-prop-1-ene CH2=CH 87 CH-O-CO-NH2 3-methylamino-carboxy-prop-1-ene CH2=CH 80 1.4430 CH2-O-CO-NH-CH3 3-i-propylamino-carboxy-prop-1-ene CH2=CH 40 1.4408 CH2-O-CO-NH-CH- (CH3) 2 3-butylamino-carboxy-prop-1-ene CH2=CH 83 1.4490 i CH2-0-CO-NH- (CH2) 3CH3 3-cyclohexylamino-carboxy-prop-1-ene c~-o-cD-D-@ 90 30-32 1 C/1ECH 3-phenylamino-carboxy-prop-l-ene'/ ? \ 65 70 1

Yield Melting % point: C 3,4-bis-(methyl-aminocarboxy)-but-1-ene CH2 = CH-(H-O-CO-NtI-CH3 85.7 66-70 CH2-0-CO-NH-CH3 3,4-bis-(isopropyl-aminocarboxy)-but-1-ene CH2 = CH-CH-O-CO-SE-CH-fCH.) * 87 96-99 CH2-O-CO-NH-CH-(CH3) a 3,4-bis-(butyl-aminocarboxy)-but-1-ene CH2 =-CH-CH-O-CO-NH-(CH2) 3CH3 81.2 45 CH2-O-CO-2stH-(CH2) 3-CH3 3,4-bis- (cyclohexyl-aminocarboxy)-but-1-ene D-sH > O'IZ-O. CJ~N 3,4-bis-(phenyl-aminocarboxy)-but-1-ene Ct12 CH H 81 121-23

Yield Melting nD % point: C 2-methylaminocarboxy-ethyl CH3 68 1.4590 methacrylateCH2 = C COO-CHz-CH2-O-CO-NH-CH3 2-isopropylaminocarboxy-ethyl CH, 69.3 54.57 methacrylateCH2=C COO-CH2-CH2-O-CO-NH-CH-(CH3) 2 2-butylaminocarboxy-ethyl CH3 86 1.4602 methacrylateCH2=C COO-CH2-CH2-O-CONH-(CH2) 3CH3 2-cyclohexylaminocarboxy-ethyl/C' 71 44-51 methacrylatecHz =c CDO'Gi2-CHj-O'CO'NH 2-phenylaminocarboxy-ethyl 85 40-42 methacrylateCt. 5 c"c.

C Cz2 Crl2 0 CO rs U

Yield Melting nD % point : C 2-methylaminocarboxy-ethyl acrylate CH2=CH 86.5 1.4630 1 COO-CH2-CH2-O-CO-NH-CH3 2-isopropylaminocarboxy-eshyl acrylate CH2-CH 63 34-37 COO-CH2-CH2-O-CO-NH-CR-(CH3) 2 2-butylaminocarboxy-ethyl acrylate CH2= ICH 71 1.4609 COO-CH2-CH2-0-CO-NH- (CH2) 3CH3 2-cyclohexylaminocarboxy-ethyl acrylate c82=c. 1 65. 6 C)-4 C4 2-phenylaminocarboxy-ethyl acrylate i/ ? \ 88. 5 59 CDO-CHp-Uiz-O-CD-rH O The following Examples illustrate the preparation of polymers which may be incorporated in pharmaceutical compositions of the present invention.

Example 1 A. Preparation of Copolymer with repeating unit of the formula

430 parts by weight of 1, 3-diacetoxy-2-methylene-propane, 245 parts by weight of maleic anhydride and 15 parts by weight of tert.-butyl peroctoate are dissolved in 1,200 parts by volume of ethyl acetate. After stirring for 6 hours at 80 C, the viscous solution is allowed to cool and is sprayed into 3,000 parts by volume of benzene, and the polymer which is precipitated is filtered off and dried.

Yield: 655 parts by weight = 97% of theory.

Softening point : 164-183 C ; rel. : 1.08.

B. Saponification to produce the Na salt of the corresponding polymeric carboxylic acid with repeating unit of the formula

180 parts by weight of sodium hydroxide are dissolved in 2,000 parts by volume of methanol. 540 parts by weight of the copolymer prepared according to part A above are then introduced in portions and the resulting suspension is heated to 65 C. After 4 hours, the solid is filtered off, washed until neutral and dried.

Yield: 485 parts by weight = 97.8% of theory.

Example 2 Preparation of Copolymer with repeating unit of the formula

210 parts by weight of N-vinylpyrrolidone and 90 parts by weight of 1,3-bis (methylaminocarboxy) 2-methylenepropane are dissolved in 1,000 parts by volume of benzene and the solution is warmed to 80 C. After adding 3 parts by wieght of azodiisobutyronitrile, the mixture is stirred for 3 hours. During this time, the polymer precipitates, and it is filtered off, rinsed with benzene and dried.

Yield : 285 parts by weight = 95% of theory.

Softening point: 183-187 C 71rel. : 1.11 (1 g/100 ml of DMF at 20 C), 1.81 (5 g/100 ml of DMF) and 2.41 (10 g/100 ml of DMF.

Example 3 Preparation of Copolymer with repeating unit of the formula

20 parts by weight of 1, 3-bis- (methylaminocarboxy)-2-methylenepropane and 20 parts by weight of dimethylaminoethyl methacrylate are dissolved in 200 parts by volume of water, and 0.8 part by weight of azodiisobutyronitrile added thereto. The mixture is warmed to 70-75 C for 2 hours, whilst stirring. The polymers in solution are isolated, after cooling, by precipitation in 1,000 parts by volume of acetone. After filtering off and rinsing the product, it is dried in vacuo at 50 C.

Yield : 35.2 parts by weight = 88% of theory.

Softening point: 90-93 C.

Example 4 Preparation of Polymeric 1, 3-bis- (methylamino-carboxy)-2-methylenepropane of the formula

wherein n is a large number.

2 parts by weight of di-tert.-butyl peroxide are added to 100 parts by weight of 1,3 bis- (methylamino-carboxy)-2-methylenepropane and the mixture is warmed to 130 140 C for 5 hours. The resulting viscous polymer is then purified by pouring into and stirring with, ethyl acetate. After decanting off the solvent, the homopolymer is dried.

Yield: 83 parts by weight = 83% of theory.

Softening point: 122-130 C.

Example 5 Preparation of Copolymer of 1, 3-diacetoxy-2-methylenepropane and N-vinyl-pyrrolidone with repeating unit of the formula

The polymer is prepared according to Example 2. It is a white hygroscopic powder with a softening point of 152-160 C and a K value of 24. The polymer consists of 1,3diacetoxy-2-methylenepropane to the extent of 28% and N-vinylpyrrolidone to the extent of 72%, determined by nitrogen analysis.

The yield is 90%.

Example 6 Preparation of Copolymer of 1, 3-diacetoxy-2-methylenepropane and vinyl acetate with repeating unit of the formula

Vinyl acetate and 1, 3-diacetoxy-2-methylenepropane are polymerised in bulk analogously to the method of Example 4. After 5 hours, the residual monomers are stripped off in vacuo and the clear highly viscous polymer is poured out. It solidifies at room temperature to give a brittle glass-like product with a K value of 47.5. Saponification yields the corresponding polyol which is water-soluble.

Yield: 92%-are. : 1.61.

Example 7 Preparation of Terpolymer of styrene, maleic anhydride and 1, 3-diacetoxy-2methylenepropane with repeating unit of the formula

The polymer, prepared by a method similar to that described in Example 2, has a K value of 57 and a softening point of 208-215 C and is obtained in 78% yield. After saponifying to give the Na salt of the corresponding polymeric carboxylic acid, the polymer is water-soluble.

Example 8 Preparation of Copolymer of 1, 3-dipropioxy-2-methylenepropane and acrylic acid with repeating unit of the formula

A white powder, which is prepared by a method similar to that described in Example 2, with a K value of 52 and a softening point of 176-184 C is obtained in 78% yield.

Example 9 Preparation of Copolymer of 1, 3-dipropioxy-2-methylenepropane and Nvinyl-pyrrolidone with repeating unit of the formula

30% by weight of 1, 3-dipropioxy-2-methylenepropane and 70% by weight of N-vinylpyrrolidone are polymerised by a process analogous to that described in Example 2. The polymer is a white hygroscopic water-soluble powder with a softening point of 156-162 C.

Yield : 88% Example 10 Preparation of Copolymer of 1, 3-dipropioxy-2-methylenepropane and acrylamide with repeating unit of the formula

If 50% by weight of 1, 3-dipropioxy-2-methylenepropane and 50% by weight of acrylamide are polymerised by a method analogous to that described in Example 2, a water-soluble white powder is obtained.

Yield : 87%; Softening point: 267-283 C.

Example11 Preparation of Copolymer of 1, 3-dibenzoxy-2-methylenepropane and Nvinyl-pyrrolidone with repeating unit of the formula

30% by weight of 1, 3-dibenzoxy-2-methylenepropane and 70% by weight of N-vinylpyrrolidone are polymerised by a method analogous to that described in Example 3.

Yield: 95% 7) rel. : 1.11 Softening point: 183-195 C.

Example 12 Preparation of Copolymer of 1, 3-dibenzoxy-2-methylenepropane and acrylic acid with repeating unit of the formula

50% by weight of 1, 3-dibenzoxy-2-methylenepropane and 50% by weight of acrylic acid are polymerised by a method analogous to that described in Example 2.

Yield: 70 % K value : 52 Softening point: 164-170 C Xrel. : 1.74 Example 13 Preparation of Copolymer of 1, 3-dibenzoxy-2-methylenepropane and acrylamide with repeating unit of the formula

If 50% by weight of 1, 3-dibenzoxy-2-methylenepropane and 50% by weight of acrylamide are polymerised by a method analogous to that described in Example 2, a white water-soluble polymer with a softening point of 300 C is obtained in 75% yield.

Example 14 Preparation of Copolymer of 1, 3-bis- (amino-carboxy)-2-methylenepropane and N-vinylpyrrolidone with repeating unit of the formula

The copolymer of 30% by weight of 1, 3-bis- (aminocarboxy)-2-methylenepropane and 70% by weight of N-vinylpyrrolidone is prepared by a method analogous to that described in Example 2.

Yield : 94% K value: 25 -are. : 1.20.

Example 15 Preparation of Copolymer of 1, 3-bis- (amino-carboxy)-2-methylenepropane and maleic anhydride with repeating unit of the formula

If 50% by weight of 1, 3-bis- (aminocarboxy)-2-methylenepropane and 50% by weight of maleic anhydride are copolymerised by a method analogous to that described in Example 2, a white powder, which after saponifying to give the Na salt of the corresponding polymeric carboxylic acid is water-soluble, is obtained in 60% yield.

Exempte 16 Preparation of Copolymer of 1, 3-bis-(methylamino-carboxy)-2-methylenepropane and vinyl acetate with repeating unit of the formula

50% by weight of 1, 3-bis-(methylamino-carboxy)-2-methylenepropane and 50% by weight of vinyl acetate are copolymerised in bulk.

Yield : 60% Softening point: 76-80 C K value : 30 rrel. : 1.25 (1 g/100 ml of DMF, 20 C) After saponifying to give the corresponding polyol, the polymer is water-soluble.

Example 17 Preparation of Copolymer of 1, 3-bis-(methylamino-carboxy)-2-methylenepropane and maleic anhydride with repeating unit of the formula

On polymerisation of 50 mol % of 1, 3-bis- (methylamino-carboxy)-2- methylenepropane and 50 mol % of maleic anhydride by a method analogous to that described in Example 2, the desired polymer with a softening point of 131-147 C is obtained in a yield of 87%. Saponification to give the Na salt of the corresponding polymeric carboxylic acid, which is water-soluble, is then carried out.

Example 18 Preparation of Terpolymer of styrene, maleic anhydride and 1,3-bis (methylaminocarboxy)-2-methylenepropane with repeating unit of the formula

25 mol % of styrene, 50 mol % of maleic anhydride and 25 mol % of 1,3-bis (methylamino-carboxy)-2-methylenepropane are polymerised by a method analogous to that described in Example 2. The resulting polymer has a K value of 30 and a softening point of 195-230 C.

The yield is 93% Saponification to give the Na salt of the corresponding polymeric acid which salt is water-soluble, is then carried out.

Example 19 Preparation of Copolymer of 1, 3-bis- (iso-propylamino-carboxy)-2-methylenepropane and N-vinylpyrrolidone with repeating unit of the formula

30% by weight of 1, 3-bis- (iso-propylamino-carboxy)-2-methylenepropane and 70% by weight of N-vinylpyrrolidone are polymerised by a method analogous to that described in Example 1.

Yield : 94% 71rez. : 1. lu.

Example 20 Preparation of Copolymer of 1, 3-bis- (propylamino-carboxy)-2-methylenepropane and maleic anhydride with repeating unit of the formula

50 mol % of 1, 3-bis- (propylamino-carboxy)-2-methylenepropane and 50 mol % of maleic anhydride are polymerised by a method analogous to that described in Example 2.

Yield: 91 % Softening point: 148 C Saponification to give the Na salt of the corresponding polymeric carboxylic acid which salt is water-soluble, is then carried out.

Example 21 Preparation of Copolymer of 1, 3-bis- (cyclohexylamino-carboxy)-2-methylenepropane and maleic anhydride with repeating unit of the formula

50 mol % of 1, 3-bis- (cyclohexylamino-carboxy)-2-methylenepropane and 50 mol % of maleic anhydride are polymerised by a method analogous to that described in Example I.

Yield : 62% 77rez. : 1. 18 Saponification to give the Na salt of the corresponding polymeric carboxylic acid which salt is water-soluble, is then carried out.

Example 22 Preparation of Copolymer of 1, 3-bis- (cyclohexylamino-carboxy)-2-methylenepropane and N-vinylpyrrolidone with repeating unit of the formula

30% by weight of 1, 3-bis- (cyclohexylamino-carboxy)-2- methylenepropane and 70% by weight of N-vinylpyrrolidone are polymerised by a method analogous to that described in Example 1.

Yield: 96% 71rez. : 1.12.

Example 23 Preparation of Copolymer of 1, 3-bis-(phenyiarnino-carboxy)-2-methy!enepropane and N-vinylpyrrolidone with repeating unit of the formula

30% by weight of 1, 3-bis- (phenylamino-carboxy)-2-methylenepropane and 70% by weight of N-vinylpyrrolidone are polymerised by a method analogous to that described in Example 2. The polymer is water-soluble and has a K value of 23.

Yield: 92% 71rez : 1.18.

Example 24 Preparation of Copolymer of 1, 3-bis-(phenylamino-carboxy)-2-methylenepropane and maleic anhydride with repeating unit of the formula

50 mol % of 1, 3-bis- (phenylamino-carboxy)-2-methylenepropane and 50 mol % of maleic anhydride are polymerised by a method analogous to that described in Example 2.

Yield: 72% Softening point: 118-121 C.

Saponification to give the Na salt of the corresponding polymeric carboxylic acid which salt is water-soluble, is then carried out.

Example 25 Preparation of Copolymer of acrylamide and carbamic acid allyl ester of the formula

wherein n is a large number.

20.2 parts by weight of carbamic acid allyl ester and 14.2 parts by weight of acrylamide are dissolved in 100 parts by weight of benzene. After adding 0.35 part by weight of azodiisobutyronitrile thereto, the mixture is warmed to 80 C and stirred for 6 hours. During this time, the polymer precipitates, and it is filtered off, rinsed and dried.

Yield: (79% of theory) Softening point : 270 C Example 26 Preparation of Copolymer of acrylic acid and 3-phenyl-amino-carboxy-prop-I-ene with repeating unit of the formula

50 mol % of acrylic acid and 50 mol % of 3-phenyl-aminocarboxy-prop-l-ene are polymerised by a method analogous to that described in Example 1.

Yield : 85% Softening point: 128-150 C 7) rel. : 1.45 Example 27 Preparation of Copolymer of acrylamide and 3,4-bis- (methyl-amino-carboxy)-but-l-ene of the formula

wherein n is a large number.

50 mol % of acrylamide and 50 mol % of 3X4-bis-(methylamino-carboxy)-but-l-ene are polymerised by a method analogous to that described in Example 1.

Yield : 73% Softening point: 197-200 C Example 28 Preparation of Copolymer of N-vinylpyrrolidone and 3,4-bis- (methyl-amino-carboxy)but-l-ene of the formula

wherein n is a large number.

If 50 mol % of 3,4-bis- (methyl-aminocarboxy)-but-l-ene and 50 mol % of N-vinylpyrrolidone are polymerised by a method analogous to that described in Example 1, a white water-soluble polymer with a softening point of 110-112 C is obtained in 87% yield.

Tre). : 1. 07 Example 29 Preparation of Copolymer of acrylamide and 3,4-bis- (butyl-amino-carboxy)-but-l-ene of the formula

wherein n is a large number.

The copolymer of 50 mol % of acrylamide and 50 mol % of 3,4-bis- (butylaminocarboxy)-but-l-ene is prepared by a method analogous to that described in Example 1.

Yield : 66% Softening point: 270-277 C Example 30 A. Preparation of Copolymer of 2-hydroxy-ethyl methacrylate and maleic anhydride of the formula

wherein n is a large number.

60 parts by weight of 2-hydroxy-ethyl methacrylate, 49 parts by weight of maleic anhydride and 1 part by weight of tert.-butyl peroctoate are dissolved in 500 parts by weight of ethyl acetate and the solution is warmed to 80 C. The polymer precipitates in the course of 6 hours. It is filtered off, rinsed with ethyl acetate and dried.

Yield: 92 parts by weight (84% of theory) B. Saponification to give the Na salt of the corresponding polymeric carboxylic acid with repeating unit of the formula

40 parts by weight of sodium hydroxide are dissolved in 500 parts by volume of methanol. 100 parts by weight of the copolymer prepared according to part A above are then introduced in portions and the resulting suspension is heated to 65 C. After 4 hours, the solid is filtered off, washed until neutral and dried.

Example 31 Preparation of Polymeric 3,4-bis-(methylaminocarboxy)-but-l-ene with repeating unit of the formula

2 parts by weight of di-tert.-butyl peroxide are added to 100 parts by weight of 3,4 bis- (methyl-aminocarboxy)-but-l-ene and the mixture is warmed to 130-140 C for 5 hours. The resulting viscous polymer is then purified by pouring into and stirring with ethyl acetate. After decanting off the solvent, the homopolymer obtained is dried.

Yield : 86 parts by weight = 86% of theory.

Example 32 Preparation of Copolymer of N-vinylpyrrolidone and 3-methylaminocarboxy-prop-l-ene with repeating unit of the formula

70 parts by weight of vinylpyrrolidone and 30 parts by weight of 3-methylaminocarboxy-prop-1-ene are dissolved in 250 parts by volume of benzene and the solution is warmed to 80 C. After adding I part by weight of azodiisobutyronitrile, the mixture is stirred for 5 hours and the polymer precipitates and is filtered off and dried.

Yield : 93 parts by weight = 93% of theory.

A particularly preferred composition according to the present invention is one in which the water-soluble polymer has a repeating unit of the general formula

wherein in each of the formulae (I'), (II') and (III') R is H,-C-R'or-C-NH-R", ,.

0 0 wherein R'is alkyl, cycloalkyl or aryl, and R"denotes hydrogen, alkyl, cycloalkyl or aryl, Y and Z are the same or different and each is a radical of a monomer which can be copolymerised with 1, 3-dihydroxy-2-methylenepropane or a derivative thereof, said monomer (s) being such that the resulting homopolymer or copolymer is substantially water-soluble, n denotes from 30 to 99 mol m denotes from 1 to 70 mol %, q denotes from 30 to 99 mol %, p denotes from 1 to 65 mol % and r denotes from 65 to 1 %.

Claims (27)

WHAT WE CLAIM IS:

1. A pharmaceutical composition containing as an active ingredient a compound which is a water-soluble homopolymer or copolymer which polymer incorporates radicals of one or more, respectively, unsaturated monohydroxy and/or polyhydroxy compounds and/or derivatives thereof, wherein the water-soluble polymer has a repeating unit of the general formula

wherein in each of the formulae I to IV

R is hydrogen,-C-alkyl,-C-cycloalkyl,-C-aryl O (t i 0 0 0 -C-NH2,-C-NH-alkyl,-C-NH-cycloalkyl or-C-NH-aryl, /'") ! O O O O A is hydrogen or methyl, B is hydrogen or methyl, Y and Z are the same or different and each is a radical or a monomer which can be copolymerised with an unsaturated monohydroxy or polyhydroxy compound or derivative thereof, said monomer (s) being such that the resulting homopolymer or copolymer is substantially water-soluble, p denotes from 30-100 mol %, q denotes from 0-70 mol % and r denotes from 0-70 mol %, or where Y and/or Z includes a carboxylic acid group, a pharmaceutically acceptable salt thereof, in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent or a molecular weight less than 200 except in the presence of a surface-active agent.

2. A composition according to Claim 1 wherein the water-soluble polymer has a repeating unit of the general formula

wherein R is hydrogen,-C-alkyl,-C-cycloalkyl,-C-aryl xi 11 11 11 -C-NH2,-C-NH-alkyl,-C-NH-cycloalkyl or-C-NH-aryl, u If 1) il O O O O Y and Z are the same or different and each is a Artwork supplied radical of a monomer which can be copolymerised with 1,3dihydroxy-2-methylenepropane or a derivative thereof, said monomer (s) being such that the resulting homopolymer or copolymer is substantially water-soluble q denotes from 30 to 100 mol %, p denotes from 0 to 70 mol % and r denotes from 0 to 70 mol %.

3. A composition according to claim 1 wherein the water-soluble polymer has a repeating unit of the general formula (II), (III) or (IV) as defined hereinbefore.

4. A composition according to any of the foregoing claims wherein Y and Z are each a radical of maleic acid, maleic anhydride, fumaric acid, acrylic acid, optionally in the form of a salt, acrylamide, fumaric or maleic acid half-amides, optionally in the form of a salt, styrene, hydroxyalkyl acrylate and methacrylate, sulphoalkyl acrylate and methacrylate, vinylpyrrolidone, vinylcaprolactam, vinylpyridine, vinyl-imidazole, allylhydantoin or salicylic acid methacrylate.

5. A composition according to claim 2 in which the active ingredient is any compound having a repeating unit of formula I as defined hereinabove which is hereinbefore specifically mentioned.

6. A composition according to claim 3 in which the active ingredient is any compound having a repeating unit of formula (II), (III) or (IV) as defined hereinabove which is hereinbefore specifically mentioned.

7. A composition according to claim 1 in which the active ingredient is a compound with a repeating unit of the formula (VIII"')

8. A composition according to claim I in which the active ingredient is any compound as defined in claim I which is hereinbefore specifically mentioned other than those mentioned in in claims 5 to 7.

9. A pharmaccutical composition containing as an active ingredient a compound as defined in any of claims ! to 8 in the form of a stérile and/or isotonic aqueous solution.

10. A pharmaceutical composition according to claim 9 in the form of a solution in physiological sodium chloride.

11. A composition according to any one of claims I to l () contiining from 0.5 to 95% of the active ingredient hy weigh).

12. A medicament in dosage umt form comprising a compound us defined in any of claims I to 7.

13. A medicament in the form ot tal lots, pills, dragees, capsules, ampoules, or sup positories comprising a compound as defincd in any of claims 1 to 7.

14. A médicament in dosage unit form comprising a compound as defined in claim 2.

15. A medicament in dosage unit form comprising a compound as defined in claim 3.

16. A method of combating tumours in non-human animals which comprises administering to the animals a compound as defined in any of claims I to 8 either alone or in admixture with a diluent or in the form of a medicament according to claim 12 or 13.

17. A method according to claim 16 wherein the compound is as defined in claim 2.

18. A method according to claim 16 wherein the method is as defined in claim 3.

19. A method according to any one of claims 16 to 18 in which the active compound is administered in an amount of 0. 5 to 500 mg per kg body weight per day.

20. A method according to any claims 16 to 19 in which the active compound is administered parenterally.

21. A method according to claim 20 wherein the active compound is administered intravenously, intramuscularly or intraperitoneally.

22. A composition according to claim 1 wherein the water soluble polymer has a repeating unit of the general formula

wherein in each of the formulae (I'), (II') and (III')

wherein R'is alkyl, cycloalkyl or aryl, and R"'denotes hydrogen, alkyl, cycloalkyl or aryl, Y and Z are the same or different and each is a radical of a monomer which can be copolymerised with 1, 3-dihydroxy-2-methylenepropane or a derivative thereof, said monomer (s) being such that the resulting homopolymer or copolymer is substantially water-soluble n denotes from 30 to 99 mol %, m denotes from 1 to 70 mol %, q denotes from 30 to 99 mol %, p denotes from 1 to 65 mol % and r denotes from 65 to I mol %.

23. A composition according to claim 22 in which the active ingredient is any com pound having a repeating unit of formula (I'), (II') or (III') as defined hereinabove which is herein before specifically mentioned.

24. A pharmaceutical composition containing as an active ingredient a compound as defined in claim 22 or claim 23 in the form of a sterile and/or isotonic aqueous solution.

25. A medicament in dosage unit form comprising a compound as defined in claim 22 or claim 23.

26. A medicament in the form of tablets, pills, dragees, capsules, ampoules, or suppositories comprising a compound as defined in claim 22 or claim 23.

27. A method of combating tumours in non-human animals which comprises administering to the animals a medicament according to claim 25 or 26.