JPS6136494B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to the use of certain known water-soluble homopolymers and copolymers as antitumor agents. Already copolymerized Cu〓 of ethylene maleic acid and
Co〓 complex is Walker sarcoma (Walker sarcoma)
[J.Med.Chem., Vol. 12 (1969), p. 1118]. Polyethylene sorbitan monooleate (Tween 80) has already been used to immunize Ehrlich tumors with abnormal chromosomes [Experimentia, Vol. 29 (1973), p. 701. ]. Additionally, various types of polycateions, such as polyamidoamine, poly-N-monophinoethyl acrylamide, and N-oxide polymers, have been tested in preventing the formation of metastases, but they are only effective in migrating tumor cells and are effective in preventing tumor cell migration at that location. generation of metastases,
It has also been found that it has no effect on the generation of lymph node metastases [Journal of Medicinal Chemistry, Vol. 16 (1973), p. 496]. Furthermore, the activity of a polymer having a carboxyl group against Sarcoma 180 has been described as a function of its molecular weight, charge density of the polycarboxyl group, and metal binding ability [Intern Ph.D. Dissertation Abstract B33
(1973) 5745]. Polyanions such as polyammonium acrylate, acrylamide, and ethylene/maleic anhydride copolymers are associated with antitumor activity;
It exhibits heparin-like and antiviral effects and is also thought to increase immune responsiveness. [Journal of Medicinal Chemistry, Vol. 17 (1974), p. 1335]. Other researchers are macrophage
Prevention of cytotoxicity of quartz on culture medium [Brit. J. Pharmacol., Vol. 8, (1970)], sterically different molecules depending on experimental conditions. We are examining the difference in the effects of Condensation product of polyoxypropylene and polyoxyethylene [Pluronic]
F68] has been shown to be active against Walker 256 Ascite tumors (Cancer, vol. 29 (1972), p. 171), presumably by affecting coagulability. N-pril- (or pyrimidyl)-N-pril-
In a treatment experiment for Sarcoma 180 using a polymerized pyrimidine compound of the pyrimidylethylenediamine type, survival time of tumor-bearing mice was reduced by 25%.
It has been found that the molecule can be lengthened by an additional 1
Introducing -deoxy-ribose-5-fluoropyrimidine increases its action. As can be seen from the above studies, the antitumor effects of previously studied polymers on experimental tumors are often only at the low end of significance and are often limited to prophylactic or adjunctive effects. Although the preliminary studies described above were often carried out on murine tumors, such experiments in any case have a regression effect of nature, are systematic and performed under conditions similar to clinical conditions. Not yet. Although in most cases there is no data on the toxicity of the compositions, incomplete excretion and storage in the tissues can be expected when giving high doses of substances with a molecular weight of more than 30,000. In the present invention, at least partially unsaturated mono- or polyhydroxy compounds or derivatives thereof, such as esters or urethanes, such as 1,3-dihydroxy-2-methylenepropane and/or derivatives thereof (see German Patent Application No.
It has been found that water-soluble homopolymers and copolymers made from 2332562) have potent antitumor activity. Surprisingly, in the molecular weight range of 1000 to 50000, these substances can be administered over a wide range of doses from 0.5 to 500 mg/Kg, preferably from 5 to 250 mg/Kg, under experimental conditions and in a dosing regimen resembling clinical conditions. It shows significant therapeutic activity in solid tumors in proliferative systems. The therapeutic range of action of these substances is therefore unusually wide [LD ₅₀ (intravenous administration): 5000 mg/Kg, therapeutic dose:
0.5~500mg/Kg]. The drug of the present invention therefore represents an important development in the field of pharmacy. According to the invention, one or more groups of unsaturated monohydroxy and/or polyhydroxy compounds and/or derivatives thereof, or salts thereof, if the groups contain acidic or basic groups, are attached. containing as active ingredient a water-soluble homopolymer or copolymer with which it is mixed with a solid or liquefied gaseous diluent or a liquid diluent other than a solvent with a molecular weight lower than 200, excluding any surfactants present. A pharmaceutical composition is provided. Particularly suitable active compounds for the compositions of the invention are of the general formula However, in the formula, R is H,

[expression] or

[Formula], R' is alkyl, cycloalkyl or aryl, R'' is hydrogen, alkyl, cycloalkyl or aryl, A is hydrogen, methyl, B is hydrogen or methyl, Y and Z are the same or different. and is a monomer group copolymerizable with an unsaturated monohydroxy or polyhydroxy compound or a derivative thereof, respectively;
The monomer is such that the homopolymer or copolymer obtained is substantially water-soluble, p is 10 to 100 mol%, q is 0 to 90 mol%, and r is 0 to 90. A water-soluble homomonomer or copolymer having mol % of repeating units. In one embodiment of the invention, the water-soluble homopolymer or copolymer is 1,3-dihydroxy-2-
Compositions containing methylpropane and/or derivatives thereof are provided. The copolymerizable monomers Y and Z used to prepare the compounds of formulas are, for example, maleic acid, maleic anhydride, fumaric acid, acrylic acid, optionally salts thereof, acrylamide, fumaric acid or half-amides of maleic acid. , optionally its salts, styrene, hydroxyalkyl acrylates and methacrylates, sulfoalkyl acrylates and methacrylates, vinylpyrrolidone, vinylcaprolactam, vinylpyridine, vinylimidazole, allylhydantoin or salicylic acid methacrylate. The proportions of the individual copolymerizable monomers that make up the copolymers useful in the present invention can vary within wide limits. However, the composition must be chosen so that a water-soluble copolymer results. Homopolymers or copolymers containing unsaturated monohydroxy or polyhydroxy and/or derivatives thereof, or repeating units thereof, to be used in the present invention are as follows. The unsaturated monohydroxy and polyhydroxy compounds used in the polymer in the present invention are known compounds. From these substances by known methods,
Many derivatives can be prepared, for example by esterification, and the corresponding urethanes by reaction with isocyanates. Homopolymers and copolymers may contain peroxides such as benzoyl peroxide, di-t-butyl peroxide, dilauroyl peroxide, dicumyl peroxide, t-butyl hydroperoxide, cumene hydroperoxide or diacetyl peroxide, Carboxylic acid esters (e.g. t-butyl peracetate, perbenzoate, peroctoate, perpivalate or perisobutyrate), percarbonates (e.g. isopropyl peroxide-dicarbonate or ethylhexyl percarbonate), arylsulfonyl peroxides (e.g. acetyl cyclohexane sulfonyl peroxide) or azo compounds (eg azodiisobutyronitrile) from monomers by free radical polymerization. In principle, all customary polymerization methods can be used, but bulk polymerization, solution polymerization and precipitation polymerization are preferred. In particular, homopolymers are advantageously obtained by polymerization in bulk; solution and precipitation polymerizations are preferred in the case of copolymers and terpolymers. However, unsaturated hydroxy compounds themselves cannot be homopolymerized or copolymerized. However, homopolymers or copolymers containing free hydroxyl groups can be prepared by homopolymerizing or copolymerizing the corresponding esters and then saponifying the ester groups on the polymer to hydroxyl groups, preferably by the Zemplen process. It can be manufactured using Compounds of the invention that are acids or bases and their pharmaceutically acceptable salts can be interconverted by any suitable method; such interconversion methods are well known in the art. A preferred salt of the polymers of the invention containing carboxylic acid groups is the sodium salt. The compounds of the present invention have strong antitumor properties against tumors in animals and humans, and have extremely low toxicity, so they can be used to control diseases caused by tumors. As mentioned above, the invention also relates to the use of the compounds of the invention in medicine and veterinary medicine. The compounds according to the invention are used as active ingredients in a mixture with a liquid diluent other than a solvent, with a molecular weight of less than 200 (preferably less than 350), unless a solid or liquefied gaseous diluent or a surfactant is present. It can be incorporated into a pharmaceutical composition. Furthermore, the compound of the present invention can be incorporated as an active ingredient in the form of a sterile or isotonic aqueous solution to form a pharmaceutical composition. The compounds of the invention can also be made into medicaments in the form of dosage units comprising the compounds. Medicaments containing the compounds of the invention may also be in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories. As used herein, "drug" refers to a physically separate and integral part suitable for pharmaceutical administration. As used herein, "drug in dosage unit form" refers to the daily dosage or multiple (up to 4 times) or means physically separate, integral parts suitable for pharmaceutical administration, each containing a submultiple (up to 1/40). Depending on whether the drug comprises a daily dosage or, for example, 1/2, 1/3 or 1/4 of a daily dosage, the drug is administered once or, for example, twice a day, respectively. Probably 3 or 4 times. Pharmaceutical compositions of the invention include, for example, ointments, gels, liniments, creams, sprays (including aerosols),
They may take the form of lotions, suspensions of the active ingredient in aqueous or non-aqueous diluents, solutions and emulsions, syrups, granules or powders. Diluents used in adapted pharmaceutical compositions (e.g. granules) for shaping into tablets, dragees, capsules and pills include: (a) fillers and extenders, e.g. Flour, sugar, mannitol and silicic acid; (b) Binders, such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; (c) Wetting agents, such as glycerin; (d)
Disintegrants such as agar, calcium carbonate and sodium bicarbonate; (e) Dissolution retarders such as paraffin;
(f) resorption enhancers, such as quaternary ammonium compounds; (g) surfactants, such as cetyl alcohol, glycerin monostearate; (h) adsorption carriers, such as kaolin and bentonite; (i) lubricants, such as talc. , calcium stearate and magnesium stearate and solid polyethylene glycol. Tablets, dragees, capsules and pills made from the pharmaceutical compositions of this invention may contain conventional coatings, envelopes and protective matrices, and they may contain opacifying agents. They can be constructed to release the active ingredient only or preferably in a specific part of the intestinal tract, possibly over a prolonged period of time. Coatings, envelopes and protective matrices can be made of polymeric materials or waxes, for example. The active ingredient can also be made into microcapsules together with one or more of the above diluents. Diluents used in pharmaceutical compositions suitable for shaping into suppositories include, for example, common water-soluble or water-insoluble diluents such as polyethylene glycols and fats such as cocoa oil and higher esters such as C _16
-C14 -alcohols by fatty acids]) or mixtures of these diluents. Pharmaceutical compositions of the invention which are ointments, liniments, creams and gels may, for example, contain common diluents such as animal and vegetable fats, waxes, paraffin, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, Bentonite, silicic acid, talc and zinc oxide or mixtures of these substances may be included. Pharmaceutical compositions of the invention which are powders and sprays can, for example, contain common diluents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. . Aerosol sprays can include, for example, common propellant bases such as chlorofluorohydrocarbons. Pharmaceutical compositions of the invention that are solutions and emulsions include:
For example, common diluents (excluding, of course, the above-mentioned solvents with a molecular weight below 200, unless a surfactant is present), such as solvents, solubilizers and emulsifiers; specificity of such diluents Examples are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (e.g. peanut oil), glycerin, tetrahydrofurifuryl alcohol. , polyethylene glycol and sorbitol fatty acid esters, or mixtures thereof. For parenteral administration, solutions and emulsions should be sterile and suitably sterile. Preferably the solution contains 0.05-1% W/V of active ingredient. Advantageously, solutions are prepared by dissolving the active compound in physiological saline (0.9% W/W sodium chloride in water). Pharmaceutical compositions of the invention that are suspensions may contain conventional diluents such as water, ethyl alcohol, propylene glycol, surfactants such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters. Liquid diluents, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures thereof may be included. All pharmaceutical compositions of the invention can also contain coloring and preservative agents, as well as aroma and flavor additives (eg, oil of cassava and eucalyptus) and sweetening agents (eg, saccharin). Pharmaceutical compositions generally contain from about 0.1 to 99.5%, usually from about 0.5 to 95%, by weight of active ingredient, based on the weight of the total composition. In addition to the compounds according to the invention, the pharmaceutical compositions and medicaments described above may also contain other pharmaceutically active compounds. The composition can also contain more than one of the compounds according to the invention. Any diluent in the medicament of the invention can be any diluent mentioned above for the medicament composition. Such agents can include a solvent with a molecular weight less than 200 as the sole diluent. The separate integral parts that constitute the drug are generally, by reason of their shape or packaging, adapted for pharmaceutical administration and can be, for example: tablets (including lozenges and granules), pills, dragees. , capsules, suppositories and ampoules. Some of these forms can provide sustained release of the active ingredient. Some, such as capsules, contain a protective envelope that physically separates and brings together the drug portions. A suitable daily dosage for administration of the medicament of the invention is between 25 mg and 25 g of active ingredient. The above pharmaceutical preparations and drugs are manufactured by methods known in the art, for example by mixing the active ingredients and diluent(s) to form a pharmaceutical composition (e.g. granules) and then This is done by forming the composition into a medicament (for example, a tablet). Furthermore, the compounds of the present invention can be administered to humans and non-human animals either alone or as a mixture with a diluent, or in the form of the above-mentioned drugs to control (including prevention, relief and treatment) the above-mentioned diseases in the animals. can do. It is contemplated that the active compounds may be administered orally, parenterally (eg, intramuscularly, intraperitoneally, subcutaneously or intravenously), rectally or topically, preferably intramuscularly, intraperitoneally or intravenously. Preferred pharmaceutical compositions and medicaments are therefore those adapted for parenteral administration;
For example, sterile and isotonic solutions, especially in physiological saline, and ampoules thereof. The administration method of the present invention is preferably intraperitoneal, intravenous or intramuscular administration. Generally 0.5 per day to achieve the desired results
It has been found advantageous to administer amounts of mg to 500 mg/Kg body weight, preferably 5 to 250 mg/Kg body weight. However, it is sometimes necessary to deviate from the above dosages, depending in particular on the nature and body weight of the humans and animals undergoing treatment, the individual reaction to the treatment, the type and mode of administration in which the active ingredient is administered and the course of the disease. depending on the degree or interval between doses. Thus, in some cases it may be sufficient to use less than the above-mentioned minimum dosage, while in other cases it may be necessary to exceed the above-mentioned upper limit in order to obtain the desired result. When administering large amounts, it is advantageous to divide the administration into several doses throughout the day. The substances listed in Table 2 have been tested in many experiments and under various test conditions for the induction of antitumor effects on murine Sarcoma 180, and some of them have also been tested on murine Fibrosarcoma MCS4. (Table 1). The following experimental methods (a) and (b) are described in the above two experimental tumor test methods. The data presented for experimental evaluation shows that a tumor weight index of 0.5 is considered to indicate significant or good activity. Experiment (a) Tumor test of Sarcoma MCS4 in C57B1 mice Animal species: C57B1 mice Method: Seed storage: 10~~14 days after last implantation, 0.9W/W%
Weight 20 mcs4 tumor suspension in 0.5 ml of NaCl solution
~22 g C57B1 mice were inoculated subcutaneously or intramuscularly. Immunological Screening Exam Preparation: The Last Transplant 10
After ~14 days, 8x in 0.5 ml of 0.9 W/W% NaCl solution
10 ⁵ tumor cells were inoculated subcutaneously into C57B1 mice weighing 20 g. Treatment: intraperitoneal, subcutaneous, intramuscular or intravenous injection of the required preparation solution once 7 days before tumor implantation or 7 days after implantation. Experimental period: 4 weeks after tumor implantation. The animals were then killed and the tumors closely examined. Evaluation parameters: inhibition of tumor growth. This was quantitatively determined by calculating the tumor weight index (TW index) according to the following formula: TW index = weight of tumor in treated animal group φ / weight of tumor in control group φ Assessment of results: TW index 1.0~0.8=no effect; 0.7~
0.6 = slight effect; 0.5-0.4 = moderate effect; 0.3-0.2 = good effect; and 0.1-0.0
=Extremely good effect. No recurrence at the end of the experiment = complete cure. Assessment of side effects: Measurement of animal mortality, assessment of general symptoms of experimental animals, measurement of body weight changes, recording of alpha leukocyte counts in peripheral blood and examination for macroscopic changes in organs were carried out during the course of the experiment. Experiment (b) Sarcoma in Swiss mice
180 Tumor Tests Animal Species: Swiss Mouse Method: Seed Storage: 0.9W/W%NaCl 7 days after last implantation
Sarcoma 180 ascitic cells 1x in 0.5 ml of solution
¹⁰⁶ was inoculated intraperitoneally into Swiss mice (group reared) weighing 20-22 g. Screening test preparation: Same method as for seed preservation, but subcutaneous tumor cell inoculation of 5 x 10 ⁵ ascites cells in 0.3 ml of solution. Treatment: 1 day before tumor implantation or 7 days after implantation.
Intraperitoneal, subcutaneous, intramuscular or intravenous injection of the required preparation solution. Experiment period: 28 days. The animals were then killed and the tumors closely examined. Evaluation parameters: inhibition of tumor growth. The tumor weight index (TW index) was quantitatively determined by calculation according to the following formula. TW index = tumor weight φ in treated animal group / tumor weight in control group Assessment of test results: TW index 1.0-0.3 = no effect;
0.7-0.6 = slight effect; 0.5-0.4 = moderate effect; 0.3-0.2 = good effect; 0.1-
0.0 = very good effect. No recurrence after 3 months = permanent cure. Assessment of side effects: Measurement of animal mortality, assessment of general symptoms of experimental animals, measurement of body weight changes, recording of alpha leukocyte counts in peripheral blood, and examination of macroscopic changes in organs were carried out during the course of the experiment. From the test results (tumor [TW] index) with the preparations shown in Table 1, using different dosages and administration methods and different treatment days, the drug can induce a significant tumor suppressive effect on Sarcoma 180. It is understood that it is part of the drug for fibrosarcoma MCS4.

【table】

[Table] The structural formulas of the repeating units of compounds "XI" shown in Table 1 can be found from the following Table 2.

【table】

【table】

【table】

【table】

[Table] (2) Polymer production example 1 A The following formula 430 parts by weight of 1,3-diacetoxy-2-methylenepropane, 245 parts by weight of maleic anhydride, and 15 parts by weight of t-butyl peroctoate were mixed with 1200 parts by volume of ethyl Dissolve in acetate. After stirring for 6 hours at 80° C., the viscous solution is cooled, sprayed into 3000 parts by volume of benzene, and the precipitated polymer is separated off and dried. Yield 655 parts by weight = 97% of theoretical value. Softening point 146-183℃. ζrel=1.08. B The following formula Saponification to form the Na salt of a polymerized carboxylic acid with repeating units 180 parts by weight of sodium hydroxide are dissolved in 2000 parts by volume of methanol. A small amount of 540 parts by weight of the copolymer prepared in A above was added, and the resulting suspension was heated to 65°C. After 4 hours, the solids are separated, washed until neutral, and dried. Yield: 485 parts by weight = 97.8% of theoretical value. Example 2 210 parts by weight of N-vinylpyrrolidone and 90 parts by weight of 1,3-bis-(methylaminocarboxy)-2
- Dissolve methylene propane in 1000 parts by volume of benzene and warm the solution to 80°C. After adding 3 parts by weight of azodiisobutyronitrile, the mixture was
Stir for an hour. During this time the polymer precipitates and is separated off and rinsed with benzene and dried. Yield 285 parts by weight = 95% of theoretical value. Softening point 183-187℃. ζrel: 1.11 (1 g/100 ml of DMF at 20°C), 1.81 (5 g/100 ml of DMF), 2.41 (10 g/100 ml of DMF). Example 3 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. Add 0.8 parts by weight of azodiisobutyronitrile to the solution. Spread this mixture for 2 hours at 70~
Heat to 75°C and stir during this time. After cooling the polymer in solution, 1000 parts by volume of acetone is added to precipitate it. Separate, rinse the product and dry in vacuo at 50°C. Yield 35.2 parts by weight = 88% of theory. Softening point 90-93℃. Example 4 However, in the formula, n is a large number, Process for producing polymerized 1,3-bis-(methylaminocarboxy)-2-methylenepropane 2 parts by weight of di-t-butyl peroxide
100 parts by weight of 1,3-bis-(methylaminocarboxy)-2-methylenepropane are added and the mixture is heated to 130-140 DEG C. for 5 hours. The viscous polymer obtained is purified by pouring it into stirred ethyl acetate. After decanting the solvent, the homogeneous polymer is dried. Yield 83 parts by weight = 83% of theory. Softening point 122-130℃. Example 5 1,3-diacetoxy-2- with repeating units of
Preparation of copolymer of methylenepropane and N-vinyl-pyrrolidone A polymer is prepared according to Example 2. This product is a white hygroscopic powder with a softening point of 152-160°C and a K value of 24. This polymer was determined by nitrogen analysis;
Up to 28% by weight of 1,3-diacetoxy-2-methylenepropane and 72% by weight of N-vinylpyrrolidone
Contains. Yield 90%. Example 6 1,3-diacetoxy-2- with repeating units of
Production of copolymer of methylenepropane and vinyl acetate Vinyl acetate and 1,3-diacetoxy-2-methylenepropane are bulk polymerized by the method of Example 4. After 5 hours, the residual monomer is removed in vacuo and the clear, highly viscous polymer is poured off. This solidifies at room temperature to form a brittle, glass-like product with a K value of 74.5. Saponification results in the corresponding water-soluble polyol. Yield 92%, ζrel 1.61. Example 7 A method for producing a terpolymer of styrene, maleic anhydride, and 1,3-diacetoxy-2-methylenepropane having repeating units of The temperature was 208-215°C, and the yield was 78%. The polymer becomes water-soluble when it is saponified to the corresponding Na salt of the polymerized carboxylic acid. Example 8 1,3-dipropioxy-2 with repeating units of
-Production method of copolymer of methylenepropane and acrylic A white powder having a K value of 52 and a softening point of 176 to 184°C, prepared in the same manner as in Example 2, was obtained in a yield of 78%. Example 9 1,3-dipropioxy-2 with repeating units of
-Production method of copolymer of methylenepropane and N-vinylpyrrolidone 30% by weight of 1,3-dipropioxy-2-methylenepropane and 70% by weight of N-vinylpyrrolidone are polymerized in the same manner as described in Example 2. . This polymer was a white hygroscopic water-soluble powder with a softening point of 156-162°C. Yield 88%. Example 10 1,3-dipropioxy-2 with repeating units of
-Production method of copolymer of methylenepropane and acrylamide 50% by weight of 1,3-dipropioxy-2-methylenepropane and 50% by weight of acrylamide were polymerized by the method described in Example 2 to obtain a water-soluble white powder. Ta. Yield 87%, softening point 267-283℃. Example 11 1,3-dibenzoxy-2- with repeating units of
Method for producing copolymer of methylenepropane and N-vinylpyrrolidone In the same manner as in Example 3, 30% by weight of 1,3-dibenzoxy-2-methylenepropane and 70% by weight of N-vinylpyrrolidone are polymerized. Yield 95%. ζrel 1.11. Softening point 183-195℃. Example 12 1,3-dibenzoxy-2- with repeating units of
Method for producing copolymer of methylenepropane and acrylic acid 50% by weight of 1,3-dibenzoxy-2-methylenepropane and 50% by weight of acrylic acid are polymerized in the same manner as in Example 2. Yield 70%. K value 52. Softening point 164-170℃. Example 13 1,3-dibenzoxy-2- with repeating units of
Method for producing copolymer of methylenepropane and acrylamide 50% by weight of 1,3-dibenzoxy-2-methylenepropane and 50% by weight of acrylamide were polymerized in the same manner as in Example 2 to produce a white water-soluble polymer. I got it. Yield 75. Softening point 300℃. Example 14 Method for producing 1,3-bis-(aminocarboxy)-2-methylenepropane having repeating units 30% by weight of 1,3-bis-(aminocarboxy)-2-methylenepropane and A copolymer with 70% by weight of N-vinylpyrrolidone was prepared. Yield 94%. K value 25. ζrel 20. Example 15 50% by weight of 1,3-bis-(aminocarboxy)-2-methylenepropane and 50% by weight of maleic anhydride were polymerized in the same manner as in Example 2 to obtain a white powder, which was saponified to form the corresponding Na salt of the polymerized carboxylic acid in a yield of 60%. Example 16 A method for producing a copolymer of 1,3-bis-(methylaminocarboxy)-2-methylenepropane and vinyl acetate having repeating units. 50% by weight of 1,3-bis-(methylaminocarboxy)-2-methylenepropane and 50% by weight of vinyl acetate were bulk copolymerized. Yield 60%. Softening point 76-80℃. ζrel 1.25 (1 g/100 ml DMF, 20°C) After saponification to the corresponding polyol, the polymer becomes water-soluble. Example 17 A method for producing a copolymer of 1,3-bis-(methylaminocarboxy)-2-methylenepropane and maleic anhydride having repeating units. 50 mol% of 1,3-bis-(methylaminocarboxy)-2-methylenepropane and 50 mol% of maleic anhydride were polymerized in the same manner as described in Example 2 to obtain a desired softening point of 131-147°C. 87% polymer
It was obtained in a yield of . Saponification yields the corresponding polymerized carboxylic acid Na, which is water-soluble. Example 18 Styrene, maleic anhydride and 1,3-bis-(methylaminocarboxy)- with repeating units of
A method for producing a terpolymer of 2-methylenepropane. 25 mol% styrene in the same manner as in Example 2,
50 mol% maleic anhydride and 25 mol% 1.3
-Bis-(methylaminocarboxy)-2-methylenepropane is polymerized. The obtained polymer had a K value of 30, a softening point of 195-230°C, and a yield of 93%. Saponification yields the corresponding water-soluble polymeric acid Na. Example 19 A method for producing a copolymer of 1,3-bis-(isopropylaminocarboxy)-2-methylenepropane and N-vinylpyrrolidone having repeating units. 30% by weight of 1,3-bis-(isopropylaminocarboxy)-2-methylenepropane and 70% by weight of N-vinylpyrrolidone were polymerized in the same manner as in Example 1. Yield 94%. ζrel 1.11. Example 20 A method for producing a copolymer of 1,3-bis-(propylaminocarboxy)-2-methylenepropane and maleic anhydride having repeating units. 50% by weight of 1,3-bis-(propylaminocarboxy)-2-methylenepropane and 50% by weight of maleic anhydride were polymerized in the same manner as in Example 1. Yield 91%. Softening point: 148℃. Next, it was saponified to obtain the corresponding water-soluble Na salt of the polymerized carboxylic acid. Example 21 A method for producing a copolymer of 1,3-bis-(cyclohexylaminocarboxy)-2-methylenepropane and maleic anhydride having repeating units. 50% by weight of 1,3-bis-(cyclohexylaminocarboxy)-2-methylenepropane and 50% by weight of maleic anhydride were polymerized in the same manner as in Example 1. Yield 62%. ζrel 1.18. Next, it was saponified to obtain the corresponding water-soluble Na salt of the polymerized carboxylic acid. Example 22 A method for producing a copolymer of 1,3-bis-(cyclohexylaminocarboxy)-2-methylenepropane and N-vinyl-pyrrolidone having repeating units. 30% by weight of 1,3-bis-(cyclohexylaminocarboxy)-2-methylenepropane and 70% by weight of N-vinylpyrrolidone are polymerized in the same manner as in Example 1. Yield 96%. ζrel 1.12. Example 23 1,3-bis-(phenylaminocarboxy)-2-methylenepropane and N
- A method for producing a copolymer with vinylpyrrolidone. 30% by weight of 1,3-bis-(phenylaminocarboxy)-2-methylenepropane and 70% by weight of N-vinylpyrrolidone were polymerized in the same manner as in Example 2. This polymer is water soluble and has a K value of 23. Yield 92%. ζrel 1.18. Example 24 A method for producing a copolymer of 1,3-bis-(phenylaminocarboxy)-2-methylenepropane and maleic anhydride having repeating units. 50% by weight of 1,3-bis-(phenylaminocarboxy)-2-methylenepropane and 50% by weight of maleic anhydride were polymerized in the same manner as in Example 2. Yield 72%. Softening point 118-121℃. When saponified, the corresponding polymerized carboxylic acid becomes water-soluble.
Na salt is obtained. Example 25 However, in the formula, n is a large number. A method for producing a copolymer of acrylamide and allyl carbamate ester. 20 parts by weight of carbamic acid allyl ester and 14.2 parts by weight
parts by weight of acrylamide are dissolved in 100 parts by weight of benzene. Add azodiisobutyronitrile to this
After adding 0.35 parts by weight, the mixture is heated to 80° C. and stirred for 6 hours. During this time the polymer precipitates and is separated, rinsed and dried. Yield 79%. Softening point 270℃. Example 26 A method for producing a copolymer of 3-phenylaminocarboxyprop-1-ene and acrylic acid having repeating units. Example 1: 50 mol% acrylic acid and 50 mol% 3-phenylaminocarboxyprop-1-ene
Polymerize in the same manner as. Yield 85%. Softening point 128-150℃. ζrel: 1.45. Example 27 However, in the formula, n is a large number, 3,4-bis-(methylaminocarboxy)-
A method for producing a copolymer of but-1-ene and acrylamide. 50 mol% acrylamide and 50 mol% 3.4
-bis-(methylaminocarboxy)-but-1-
and ene are polymerized in the same manner as in Example 1. Yield 73%. Softening point 197-200℃ Example 28 However, in the formula, n is a large number, 3,4-bis-(methylaminocarboxy)-
A method for producing a copolymer of but-1-ene and N-vinylpyrrolidone. 50 mol % of N-vinylpyrrolidone and 50 mol % of 3,4-bis-(methylaminocarboxy)-but-1-ene are polymerized in the same manner as in Example 1. A white water-soluble polymer was obtained. Yield 87%. Softening point 110-112℃. ζrel 1.07. Example 29 However, in the formula, n is a large number, 3,4-bis-(butylaminocarboxy)-
A method for producing a copolymer of but-1-ene and acrylamide. 50 mol% acrylamide and 50 mol% 3.4
-bis-(butylaminocarboxy)-but-1-
and ene are polymerized in the same manner as in Example 1. Yield 66%. Softening point 270-277℃. Example 30 A formula where n is a large number, and 60 parts by weight of 2-hydroxyethyl methacrylate, 49 parts by weight of maleic anhydride, and 1 part by weight of t. - Butyl peroctoate is dissolved in 500 parts by weight of ethyl acetate and the solution is heated to 80°C.
Heat to. The polymer precipitates in 6 hours. Separately, rinse with ethyl acetate and dry. Yield 92 parts by weight (84% of theory). B formula of the corresponding polymerized carboxylic acid with repeating units of
Saponification of Na salts 40 parts by weight of sodium hydroxide are dissolved in 500 parts by volume of methanol. Add a small amount of 100 parts by weight of the copolymer prepared in A above, and heat the resulting suspension to 65°C. After 4 hours, the solids are separated, washed until neutral, and dried. Example 31 Method for producing polymerized 3,4-bis(methylaminocarboxy)-but-1-ene having repeating units 2 parts by weight of di-t-butyl peroxide
Add 100 parts by weight of 3,4-bis-(methylaminocarboxy)-but-1-ene and add 5 parts of this mixture.
Heat to 130-140°C for an hour. The resulting viscous polymer is then purified by pouring into ethyl acetate and stirring. After decanting the solution, the homogeneous polymer obtained is dried. Yield 86 parts by weight = 86% of theory. Example 32 N-vinylpyrrolidone and 3-vinylpyrrolidone with repeating units of
Method for producing a copolymer with methylaminocarboxy-prop-1-ene. 70 parts by weight of vinylpyrrolidone and 30 parts by weight of 3-
Methylaminocarboxy-prop-1-ene
Dissolve in 250 parts by volume of benzene and heat the solution to 30°C. After adding 1 part by weight of azodiisobutyronitrile, the mixture is stirred for 5 hours and the polymer is precipitated, separated and dried. Yield 98 parts by weight = 93% of theory.

Claims (1)

[Claims] 1 formula In the formula, M is hydrogen or -CH ₂ -O-R, N is -CH ₂ -O-R or [formula], R is hydrogen, [formula] (C _1-4 alkyl), [formula] ] or [Formula] (C _1-4 alkyl), and Y and Z are the same or different, and each is a unit selected from maleic acid or its salt, maleic anhydride, maleic acid semiamide, acrylamide, vinylpyrrolidone, and styrene. mer group, p represents 10 to 100 mol%, q represents 0 to 90 mol%, r represents 0 to 90 mol%, and is a water-soluble polymer having repeating units of An antitumor agent characterized by containing it as an active ingredient. The antitumor agent according to claim 1, wherein 2r is 0 mol%. 3 M is CH ₂ -O-R and N is CH ₂ -O-R
and r is 0 mol%. Claim 1
The antitumor agent described in section. 4. The antitumor agent according to claim 3, wherein R is [Formula] (C _1-4 alkyl). 5. The antitumor agent according to claim 4, wherein p is about 15 to 25 mol% and q is about 75 to 85 mol%. 6 formula Claim 1 containing as an active ingredient a compound which is a water-soluble polymer having repeating units of the formula: where p represents approximately 10 to 100 mol% and q represents approximately 0 to 90 mol%. Antitumor agents as described. 7. The antitumor agent according to claim 6, wherein p is about 15 to 25 mol% and q is about 75 to 85 mol%. 8. The antitumor agent according to claim 6, wherein p is about 17 to 21 mol% and q is about 79 to 83 mol%. 9. The antitumor agent according to claim 1, which contains the compound as an active ingredient in the form of a sterile or isotonic aqueous solution. 10. The antitumor agent according to claim 9, which is in the form of a physiological sodium chloride solution. 11. The antitumor agent according to claim 1, which contains the active ingredient in an amount of 0.5 to 95% by weight. 12. The antitumor agent of claim 1 in dosage unit form containing the compound together with an inert pharmaceutical carrier. 13 Claim 12 in the form of a tablet, pill, dragee, capsule, ampoule or suppository
The antitumor agent described in section.