CH633963A5 - Antitumour composition - Google Patents

Description

The present invention relates to anti-tumor agents.

60 It has already become known that copolymeric, complex Cu11 and Co n salts of ethylene maleic acid are effective against Walker sarcoma [J. Med. Chem. 12 (1969), 1180].

Polyethylene sorbitan monooleate (Tween 80) has been used for 65 to immunize against the hyperdiploid Ehrlich-Tu-mor [Experientia 29 (1973), 710],

. Polycations of various types, e.g. Polyamide amines, poly-N-morphinoethylacrylamide and

N-oxide polymers tested for inhibition of metastasis with the result that only tumor cell seeding, but not metastasis growth in situ or lymph node metastases could be influenced [J. Med. Chem. 16 (1973), 496].

Furthermore, the effectiveness of polymers with carb-oxyl groups against sarcoma 180 depending on the molecular weight, the charge density and the metal-binding ability of the polycarboxyl groups was described [Dissertation Abstr. Intern. B 33 (1973), 5745].

Polyanions, e.g. Poly-ammonium acrylate, acrylic acid-acrylamide and copolymers of ethylene-maleic anhydride are said to have a heparin-like effect in connection with their anti-tumor activity, besides have an antiviral effect and also increase the immune reactions [J. Med. Chem. 17 (1974), 1335].

Other authors tested for prevention of the cytotoxicity of quartz on cultures of macrophages [Brit. J. Pharmacol. 38, (1970)], with differences in effects between sterically different forms of the molecule depending on the experimental setup.

A condensate of poly-oxypropylene and poly-oxyethylene (Pluronic F 68) was found to be effective against the metastasis of the Walker 256 ascites tumor, probably by influencing the ability of the blood to clot [Cancer 29 (1972), 171].

Therapeutic trials on sarcoma 180 with polymeric pyrimidine compounds of the N-puryl- (or py-rimidyl) -N-puryl-pyrimidyl-ethylenediamine type showed a 25% increase in the survival time of the tumor-bearing mice, with the additional introduction of 1-deoxy-ribose-5-fluoropyrimidine in the molecule enhanced the effect.

It emerges from all this work that the anti-tumor effect of the polymers investigated to date on the experimental tumors used often only on the lower one

3,633,963

The limit of significance lies and is in some cases only limited to prophylactic or adjuvant effects. It also appears to be disadvantageous that the cited examinations were frequently carried out on allogeneic mouse tumors tending to spontaneous regression and not systematically and under clinical settings.

There is usually a lack of information on the toxicity of the preparations, although the application of high doses of substances with a molecular weight of more than 30,000 suggests defective excretion or storage in the tissues.

It has now been found that water-soluble homopolymers or copolymers which are composed at least in part of unsaturated mono- or polyhydroxy compounds or their esters 15 or urethanes have strong antitumor properties.

The antitumor agent according to the invention is characterized by a content of at least one water-soluble homopolymer or copolymer which contains unsaturated mono- or polyhydroxy compounds or their esters or urethanes.

Surprisingly, these substances show significant curative effects on solid tumors of syngeneic systems in a broad dose range of 0.5 to 500 mg / kg, preferably 5 to 250 mg / kg, particularly in the molecular weight range from 1000 to 50,000, under experimental arrangements and types of application close to the clinic. The therapeutic range of the substances proves to be unusually large (LD 50, IV: 5000 mg / kg, therapeutic dose: 0.5 to 500 mg / kg).

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

Particularly suitable as active ingredients for the agents according to the invention are homopolymers or copolymers of the following formulas:

ch2-o-r ch - c-

^ i

"(Y Z);

(I)

ch2-0-r t-ch2-ch x (y) - (z)

^ ch2-o-r &

ch2-ch-

-(Y Z)-

(III)

ch-o-r ch2-o-r

CH2-c-

coochch2-o-r

V

B

(Y Z)-

(iv)

633963

Mean in it

R H, -OR 'or -C-NH-R ",

A li o o

R 'alkyl, cycloalkyl or aryl,

R "is hydrogen, alkyl, cycloalkyl or aryl, A is hydrogen or methyl B is hydrogen or methyl

Y and Z units of monomers polymerizable with the unsaturated homo- or polyhydroxy compounds or their esters or urethanes with the proviso that the water solubility of the copolymer is ensured,

q = 10 to 100 mol%

p = 0 to 90 mol% and r = 0 to 90 mol%.

Examples of copolymerizable monomers Y and Z that can be used are: maleic acid, maleic anhydride, fumaric acid, acrylic acid, optionally in salt form, acrylamide, fumaric or maleic acid halamides, optionally in salt form, styrene, hydroxyalkyl (meth) acrylate, sulfoalkyl ( meth) acrylate, yinyl pyrolidone, vinyl caprolactam, vinyl pyridine, yinyl imidazole, allyl hydantoin or methacrylic acid salicylate.

The proportions of the individual comonomers which build up the copolymers according to the invention can be varied within wide limits. However, the composition must be selected so that a water-soluble copolymer is formed.

Examples of homopolymers or copolymers according to the invention which contain unsaturated mono- or polyhydroxy compounds or their esters or urethanes are the following:

ch-ococh-I 1 5

CE0- c

<= i

CHjOCOCHJ

ch. 0h i 2

CH2 - Ç

ch20h cho-0-c0-nh-cht

(1 2 3

4- ch2 - ç.

ch2-0-c0-nh-ch5

4th

ch2-0-c0-ch5 ch0 - c ch - ch-

ch2-0-c0-ch3

co-nh,

cho-0-c0-cho-ch \ 2 l 5

ch0 - c ch_-ch-

2 | 2,

ch2-o-co-ch2-oh5

c00h

ch ^ -0-c0-ch_-ch

CH. -

t c

2 ~ "3

ch0 - ch

I 2 t ch2-0-c0-ch2-ch /

0—, I

cho-0-c0-cho-ch3

ch2 - c;

ch2-0-c0-ch2-ch5

CH «-

ch2-0-00- (g)

ch "-ch-ò I

c0-nh,

C.

i ch

ch - ch-

0—

n- '° 3

hn-od-o-hû

- (■ —ho-2ho ó - sho-a-

hn-oo-o-hd

"KO" MO

1 1 2

oû 00 ho-ho

ç, ho ho 0-2h0

Vo-n. «I« ko i i ho-2ho

2t f

00 00 ho ho

- ho ho 0 - 2h0

ho-2ho

J ~ 1

ho "ho

+ ■ ho - sh0 d - sho-V

^ 2 '/

ho-ho

0:

ysy ho-2ho ho - 2h0 ó - 2h0- ^

ho-2ho hn-oo-o-2ho o - 2ho-a-

^^ - HN-oo-O-2HO

î ($ ho) o-hû-oo-o-2ho

/ ô - 2ho-a-

^ ho ^ -hn-oo-o- ^ ho

^ o-hk-oo-o-2ho

I.

-f ò - 2h0 a-

v L £ z 1 '

v h0-hk-00-0-hd

2hn- ho (ovoo-o- ^ ho r 1 z N— '1 2 \ 4 ho "ho 0" ho — j—

<g ^ 00-0-2HÌ

h000 <^ ov00-0-2h0

/ 1 2 1 2 \ "f HO-HO 0" HO 4 ~

<0V00-0- * HÌ

£ 96 ££ 9

Ç

633 963

6

4th

CH2-0-C0-NH2

CH, - C

2 I

CH-O-CO-NH

CH - CH

i i

CO

co

4th

ch, -o-co-nh-ch,

i * 5

-ch_ - c ch2-o-co-kh-ch5

ch - ch-

<= i

4th

o-co-ch,

ch, -o-co-nh-ch,

i 2 3

ch2-c ch2-0-c0-nh-ch5

f ch, -o-co-nh-ch, i 2 3 _ch2 - ç

CH2 = 0 = C0- = RB «CH ^

CH2-CH

(è)

CH,

CH, -C 2 I

c00-ch2-ch2-n ^

"chJ

CH,

9-

4-

CH, -O-CO-NH-CH, i 2 3 CH, - C

£ i

CH2-0-CO-NH-CH5

CH, -CH-

^ i

° * U

4th

CH, -O-CO-NH-CH, CH_

/ i 2 3, 3 N

4-ch2 - ç ch2-c j-

CH2-0-CO-NH-CH5 CONH2

ÇH, -O-CO-NH-CH, CH,

. I «3 i 3

CH, - C CH, - C -

£ I 2 I

CH-O-CO-NH-CH 'COO

NaOOC

ch2-o-co-nh-ch5 ch

4- ch2 - c ch2 - ç ch ch

CH2-0-CO-NH-CH, COO COONa COONa

B

NaOOC

ch2-o-co-nh-ch- (ch3) 2 v ch2 - c ch2-ch -—j-

ch? -o-co-nh-ch- (ch,) 0

2 3 2 Oj]

633 963

ch2-o-co-nh-ch (ch3) 2

ch2 - c ch2-ch ch2-o-co-nh-ch (ch3) 2 oh

CÏÏO-0-C0-NH-C.HQ r? 4 9

f CH2 - c - CH2-CH — 4-

chg-o-co-SH-c ^

CHo-0-C0-NH- / ÏT \

/ l 11 \ / \

-f — ch '- c CH CH 4-

\ 2 • / - \ l I J

CH2-0-CO-NH- / h y COONa COONa

CH2-0-C0-NH-

j7 \

—F- CHn - C CH.-CH) -

v <- i / - \ ^ i y ch0 - o-co-nh- / o) / n \

^ ° * LJ

ÇH2-o-co-ra- <g>

-a ^ ch2 - c ch2-ch — j

CH2-0-C0-NH- ^ q ^!> H

ÇH2-0-C0-NH ^ \

-LCH2 - C —— CH CH j—

CH2-0-C0-NH - ^^ COONa COONa ch2-o-co-nh-ch3

-L CH_ - C CH CH 4-

v 2 i i i y

CH2-0-CO-NH-CH5 COONa COONa ch2-oh

- (- ch2 -ch ch2 - c ch ch

CH2-0H COONa COONa ch2-oh

- (- CH2 - CH CH2 - C CH CH

CH2-0H COONa COONa

CH - O-CO-NH-CH

(i 2 3 v

—CH- - C CH - CH - CH: CH 4-

^ I 0 | i i J

CH -O-CO-NH-CH COONa. COONa

-fCH ~ -CH y-

^ I

CH2-0-CO-NH-CH3

-fch2 ~ ch ch2-ch h ch2-0-c0-ch2-ch3 cooh

-fch2-ch ch2-ch

ch2-0-c0-ch2-ch3 co-nh2

4-

-fch2-ch ch2-ch-

ch9-o-co-nh-ch. ^ n>

-Û

4ch2-ch ch2-ch

ch2-0-c0-nh-ch3 ch2-nh2

4ch, -ch-

^ I

ch2-0-c0-nh-c (ch3) 3

-fch ~ -ch-

^ 1

ch2-oh

-fCH -CH-

ch2-oh

-ch2-ch-

û

; 0

-CH—

CO i

ONa

-ch i

CO

nh-c3h?

-fCH2-CH-

ch2-o-co-nh2

ch2-ch

ûr

633963

-fch2-ch ch2-ch

ch2-o-co-nh-ch3 o-co-ch3

ch-

-fCH2-CH-

CH2-c-

ch -> - o-co-nh-ch.

^ H3

coo-CH2-ch2-Nvch

CH,

i

4CH2-CH CH2_C

CH2-0-CO-NH-CH3 CONH2

4ch9-ch-

'i

CH2-0-CO-NH-CH3

CH,

I -J

ch9-c

i

- COO-

NaOOC

4CH2-CH CH CH

CH2-0-C0-NH- ^ ~ H ^ COONa COONa

-fCH2-CH CH2-CH

CH2-O-CO-NH

4CH - CH CH-j-CH-CH CH h

^ I ^ t I

CH2-0-CO-NH-CH3 COONa COONa

4ch9-ch-

^ i

CH2OH CH2OH

4CH 2 -CH

CH-O-CO-NH-CH,

CH «-0-C0-NH-CH ~ Z c,

10th

4ch9-ch-

^ i

-CH - CH-

CH-O-CO-CH-

CO-NH,

ch2-o-co-ch3

-fCH - CH-

ch-o-co-ch2-ch3 ch2-o-co-ch2-ch3

-ch ~ -ch

^ i

"Û

4CH2-CH CH2-CH

CK-0-C0- @ COOH

ch2-o-co- ^ 5)

4CH2 -CH) ■

CH-0-C0-NH-C, H_

i 3 '

CH2-0-C0-NH-C3H7

-fCH ^ -CH-

^ i

CH2-OH

-ch, -ch-

^ i

M

Cr

-fCH 2 - CH CH—

CH ~ TOH CO ONa

-CH— CO ONa

-fchph-

CH-O-CO-NH-CH.

-CH ^ -CH

* • i

CH 2 ~ 0-CO-NH-CH 3

-fCH2-CH-

ch-o-co-nh-ch3

ch2-0-c0-nh-ch3

-CH2-CH

11

633 963

-fch ~ -c z i

CH3

CH CH ~ -C CH -OH-

^ t i • «

CH-O-CO-NH-CH3 COO _ COONa COONa ch2-o-co-nh-ch3

NaOOC

-fCH2-CH-

ch-o-co-nh-ch- (ch3) 2

ch2-o-co-nh-ch- (ch3) 2

CH - CH—

-fCH9-CH-

^ i

CH-0-CO-NH-C4H9. CH2-0-CO-NH-C4H9

CH2-CH-

° tb

-fCH2-CH CH-

-CH-

t

CH-0-CO-NH-CH3 COONa COONa

CH2-0-CO-NH-CH3

-fCH - CH-

coo-ch2-ch2-o-co-nh-ch3

CH - CH— ^ •

° û

n ch3

4CH - CH - CH ~ -C) -

. j — v 2, n

C00-CH2-CH2-0-C0-NH- ^ H ^ COO> ^ g ^

NaOOC

ch3 CH3

-fCH ~ -C CH - C CH CH b

Z, z t | | n

COO-CH2-CH2-0-CO-NH-CH3 COOs. ^ \ COONa COONa

NaOOC

633 963 12

-fCH-CH CH -.- CH-

2 V ^

C00-CH2-CH2-0-C0-NH-C3H7 COONa

CH3 CH3

-ecn2-c -ch2-c hr

COO-CK 0-O-CCNH-CH -, COO-CH 0 -CH "-Nr Cil ^

i 3 2 2 \ CHJ

-fCH ~ -CH CH CH h ~

2 i / ^ \. i n ro-co- @

C00-CH-CH2-0-C0 - \ KJ) COONa COONa

The unsaturated mono- or polyhydroxy compounds contained in the homopolymers or copolymers according to the invention are known. Numerous esters can be produced from these substances by known processes by esterification and the corresponding urethanes by reaction with isocyanates.

The homopolymers and copolymers are preferably prepared from the monomers by free-radical polymerization using peroxides, for. B. benzoyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, dicumyl peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, diacetyl per-oxide, percarboxylic esters, (for example tert-butyl peracetate, -per-benzoate, -peroctoate, -perpirallynate,), Percarbonates (e.g. isopropyl peroxide dicarbonate, ethylhexyl percarbonate), arylsulfonyl peroxides (e.g. acetylcyclohexane sulfonyl peroxide) or azo compounds (e.g. azodiisobutyronitrile). Basically, all usual polymerization techniques can be used. Bulk, solution and precipitation polymerization are preferred. Homopolymers are obtained in particular by bulk polymerization; in the case of copolymers and terpolymers, solution and precipitation polymerization are preferred.

However, some unsaturated hydroxy compounds themselves cannot be homo- or copolymerized. However, homopolymers or copolymers which should contain hydroxyl groups can be prepared by homopolymerizing or copolymerizing the corresponding esters and subsequently saponifying the ester groups to give the hydroxyl groups, preferably according to Zemplén on the polymer.

With extremely low toxicity, the homo- or copolymers contained in the agents according to the invention have a strong antitumor effect against animal and human tumors and should therefore be used to combat diseases caused by tumors.

The agents according to the invention are produced by dissolving the active ingredients in physiological saline. The solutions obtained were applied intraperitoneally, intravenously or intramuscularly. The therapeutic dosage range is from 0.5 to 500 mg / kg, preferably 5 to 250 mg / kg. The unusual breadth of this area is due to the enormous non-toxicity of the active ingredients. The concentrations in which the solutions are used are accordingly 0.05 to 1%.

The substances listed in Table 2 are tested in numerous tests under various test conditions on mouse sarcoma 180, some of them also on mouse fibrosarcoma MCS 4 for the induction of tumor-25 effects (Table 1).

The methodology of the investigations on these two experimental tumors are contained in the experimental descriptions (a) and (b) below. The information on the test evaluation contained therein shows that 3o tumor weight indices <0.5 can be regarded as clear or good effects.

Experiment description a)

Tumor tests on MCS 4 sarcoma on C57B1 mice 35 Species: C57B1 mice

Procedure: stock keeping: 10-14 days after the last

Transplantation Vaccination of a tumor suspension of MCS4 in 0.5 ml 0.9% NaCl solution s. c. or i.m. on 40-257 g 40 C57B1 mice.

Preparation of immune screening tests: 10-14 days after the last transplantation, vaccination of 8 x 105 tumor cells in 0.5 ml 0.9% NaCl solution. c. on 20 g 45 C57B1 mice.

Treatment: Optionally i.p., s.c., i.m., i.v. injection of the required preparation solution 1x7 days before or 7 days after tumor transplantation.

see duration of experiment: From tumor transplantation 4

Weeks. Then killing the animals and dissecting the tumors. Evaluation parameters: inhibition of tumor growth. Quantitative determination 55 by calculating a tumor weight index

(TG index) according to the formula

TG index = 0 tumor weight of the treated animal group 0 tumor weight of the control group

60

Evaluation of the results: TG index 1.0-0.8 = no effect; 0.7-0.6 = hint of effects; 0.5-0.4 = significant effect; 0.3-0.2 = good effect; 0.1-0.0 = very good effect.

Relapse free at the end of the experiment = healing. Assessment of side effects: in the course of the experiment, determination of animal losses,

Assessment of the general condition of the test animals, determination of the change in body weight, registration of the number of leukocytes in peripheral blood, search for macroscopic changes in the organs.

Experiment description b)

Tumor tests on sarcoma 180 on Swiss mice Swiss Swiss mice

Procedure: Stockkeeping: On the 7th day after the last transplantation, vaccination of 1 x 10® ascites cells of sarcoma 180 in 0.5 ml 0.9% NaCl solution i.p. on Swiss mice weighing 20-22 g (colony breeding).

Preparation of screening tests: Same procedure as stock keeping, but tumor cell vaccination of 5 x 105 ascites cells in 0.3 ml s.c.

Treatment: Optionally i.p., s.c., i.m., i.v. injection of the required preparation solutions, 1 x in total, either on the 7th day before tumor transplantation or on the 7th day after tumor transplantation.

Test duration: 28 days. Then killing the animals and dissecting the tumors. Evaluation parameters: inhibition of tumor growth. Quantitative determination

13 633963

by calculating the tumor weight index (TG index) according to the formula

TG index = 0 tumor weight of the treated animal group 0 tumor weight of the control group

Assessment of test results: TG index 1.0-0.8 = no effect; 0.7-0.6 = hinting at location; 0.5-0.4 = significant effect; 0.3-0.2 = good effect; 0.1-0.0 =

very good effect. No recurrence after 3 months = permanent healing.

Assessment of side effects: in the course of the test, determination of animal losses, assessment of the general condition of the experimental animals, determination of changes in body weight, registration of the number of leukocytes in peripheral blood, search for ma-20 microscopic changes in the organs.

The test results with the preparations listed in Table 1 (parameters: tumor weight (TG) index) indicate that the substances on sarcoma 180, 25 a part of them and also on fibrosarcoma MCS 4 at different dosages and types of application as well as at different Treatment days are able to induce significant anti-tumor effects.

Table 1

Connective sarcoma 180 fibrosarcoma MCS 4

dung

dose

Appi.

Treat

tumor

dose

Appi.

Treat

tumor

mg / kg

lungs day *

weight

mg / kg lungs day *

weight

1 x

index

1 x

index

I.

250

i.p.

-7

0.1

25th

i.p.

- 6th

0.5

100

in the.

-7

0.2

50

in the.

- 4th

0.4

II

5

i.p.

+7

0.3

10th

i.p.

- 6th

0.6

10th

in the.

+7

0.4

50

in the.

+ 6

0.7

III

10th

i.p.

+7

0.2

100

i.p.

+ 6

0.5

10th

in the.

-7

0.2

100

in the.

+ 6

0.6

IV

250

i.p.

+7

0.3

-

-

-

-

250

in the.

+7

0.6

-

-

-

-

V

10th

i.p.

+7

0.2

-

-

-

10th

in the.

+7

0.3

-

-

-

VI

50

i.p.

-7

0.4

250

i.p.

- 7th

0.5

50

in the.

+7

0.3

10th

in the.

- 6th

0.6

VII

25th

i.p.

-3

0.3

50

i.p.

- 7th

0.4

25th

in the.

+3

0.2

-

VIII

100

i.p.

+7

0.1

100

i.p.

-MO

0.2

25th

in the.

+7

0.2

25th

in the.

+ 6

0.2

IX

1

i.v.

-7

0.2

0.05

i.v.

- 3rd

0.46

1

i.v.

+7

0.3

0.25

i.v.

- 3rd

0.52

X

1

i.v.

-7

0.36

0.05

i.v.

+ 2

0.54

5

i.v.

+7

1.09

10th

i.p.

- 7th

0.49

XI

10th

i.p.

-4

0.5

25th

i.p.

- 4th

0.41

25th

i.p.

+3

0.6

50

i.p.

+ 3

0.55

* Days

-7 =

7 days before tumor transplant

Days +7 = 7 days after tumor transplantation

The structural formulas of the compounds I to XI mentioned in Table 1 are shown in Table 2 below.

14

Table 2

/ CELOCOCH-

(1 5

—UCH2-C CH2 CH

CH2OCÖCH3

0-Ò

n ch2 ° H

—CH_-C CH CH -

V 2 I »I y n

CHo0H COONÏÏ. COONH, i 44

CH-OCONHCH,

f 1 5

- (- CH - C CH CH

V 2 1 Ii

CHjOCONHCHj COONa COONa

CB ^ OCOEUCH- COOH

/! <= 5 I

-t- CH, -C CH CHr—

x i i i 'n

CB.2OCONHCH5 C0NHCH2CH2CH2

CH, OCONHCH_ / <23 -4- CH., - CE GH, C CH

"Ù

2nd

»F

CH, OCONHCH_ 2 3

CHjOH

• Ç- CH2-C CH - CH-)

i i / n

CH20H COONa COONa

CH ^ -O-CO-NH-CH,

(1 3 \ 4cVo

CH2-0-CO-NH-CHj

CH-O-CO-NH-CH.

for \ 2 3

—V — CH, -C CH0-CH-

^ 2 | 2,

CH - 0-CO-NH-CH, N

'o-Q

-fCH 2 -CH-CH 2 -CH 2) -

0 ^ n ch-0-c0nh-ch3

ch2-o-conh-ch3

1]

4ch2-ch-ch2-ch-

* Q

ch2-0-co-nh-ch3

--f-ch ~ -ch ch - - ch-

^ I ^ t conk2 ch2-0-c0-nh2

15

Experimental part

633963

1. Monomeric yield: ° C

te%

1,3-bis (amino-carboxy) -2-methyl-çg o-co-nh 63.2 178-179

len-propane i 2 2

h9c «c

«I

ch20-c0-nh2

ch0o-co-nh-ch,

I 2 3

1,3-bis (methylamino-carboxy) -2- h_c-c 97 84-86

methylene propane 2 |

chgo-co-nh-chj ch2o-co-nh-ch (ch3) 2

1,3-bis (iso-propylamino-carboxy) - h-c-c 87 104-105

2-methylene propane 2 1

ch20-c0-nh-ch (ch5) 2

1,3-bis (propylamino-carboxy) -2-chgo-co-nh-chgchgchj 9g g3

methylene propane h "c-c

2 I

ch20-c0-nh-ch2ch2ch3

1,3-bis- (butylamino-carboxy) -2- CH20-CO-NH (CH2) 3CH3 gg 55_55

C 1

ch20-c0-nh (ch2) 3ch3

methylene propane g

2 1

CH20-C0-HN- <2)

1,3-bis (cyclohexylamino-carboxy) - H C »C 89 161-162

2-methylene propane 2 1 / - \

ch2o-co-hn / h \

) -C0-HN - <^^

ch2 °.

l, 3-bis (phenylamino-carboxy) -2- g çmç 94 129-130

methylene propane 2 I.

ch2o-co-hn-

ch ,, o-co-ch,

t <- J

1,3-diacetoxy-2-methylene-propane ch «c 82 bp

2 1 96-98 ° C

ch2o-co-ch3

ch_0-c0-hoc-ch,

1 * ^ 5

1,3-Dipropioxy-2-methylene propane h.c-c 50 nd20

I 144 (

ch2o-co-h2c-ch3

633 963

16

1. Monomeric Ext .::C

te%

ch2o-co - ((3)

1,3-dibenzoxy-2-methylene-propane H C «C

2nd 1.5521

ch2O-CO ^ Q)

3-aminocarboxypropen-1 CH2 = CH 87

ch-o-co-nh2

_ 20

3-methylamino-carboxy-propene-1 CH ~ = CH 80 rio2

z ■ 1.4430

ch2-0-c0-nh-ch3

3-i-Propylamino-carboxy-pro- ch ~ = ch 40 no20

pen-1 2 • i 4408

ch2-o-co-nk-ch- (ch3) 2

3-butylamino-carboxy-propen-l ch0 = ch 83 nD

z i 1.4490

ch2-0-c0-nh- (ch2) 3ch3

3-cyclohexylamino-carboxy-pro- ch_ = ch 90 30-32

pen-1 '/ \

ch2-o-co-nh- ^ h y

3-phenylamino-carboxy-propene-1 CH2 ~ CH 65 70

ch2-O-CO-NK - ^^

3,4-bis (methylaminocarboxy) - CH2 = CH-CH-O-CO-NH-CH3 85.7 66-70

butene-1 ch2-o-co-nh-ch3

3,4-bis- (isopropylaminocarboxy) - CH2 = CH-CH-0-CO-NH-CH- (CH-j) 2 87 96-99 bUten_1 CH2-O-CO-NH-CH- (CH3) 2nd

3,4-bis (butyl aminocarboxy) - ch., = Ch-ch-0-c0-nh- (ch-), ch., 81.2

butene-1 i ch2-o-co-nh- (ch2) 3-ch3

ch2-Q-cq-NH- ^ H "^

CH-O-CO-NH-

45

3,4-bis (cyclohexyl arainocarboxy) - CH9 = CH-CH-0-CO-NH- \ H / 85 150-153

buten-1 A '

3,4-bis (phenylaminocarboxy) - CH ~ = CH-CH-0-CO-NH-uS) 81 121-123

butene-1 2 | X = l /

17th

633 963

1. Monomeric Ext .::C

te%

ch

2-methylaminocarboxy-ethylmeth- CH = C 68 nD20

acrylate 2 \ c00-CH2-CH2-0-CO-NH-CH3 M590

ch3

2-isopropylaminocarboxy-ethyl- CH- = C ^ ..

methacrylate \ COO-CH2-CH2-O-CO-NH-CH- (CH3) 2 •

/ CH

2-butylaminocarboxy- CH ~ = C ^ ^ 6 no20

ethyl methacrylate \ 1.4602 y nC00-CH2-CH2-0-C0NH- (CH2) 3CH3

XCH3

2-Cyclohexylaminocarboxy-ethyl CH2 = C. 71 44-51

methacrylate XOO-CHj-CHj-O-CO-NH- / H \

/ ch-

2-phenylaminocarboxy-ethylmeth-qjj = C / \ 85 40- 42

2 "N: oo-ch9-ch2-o-co-nh- / 0 /

acrylate

"2" "2 x,

2-methylaminocarboxyethyl GH2 = CH 86.5 n20

acrilate œ0-CH2-CH2-0-C0-NH-CH3 - 1-4630

2-isopropylaminocarboxyethyl CH2 = CH 63 34_ 37

acrylate «: OO-Œ2-Œ2-O-OO-NH-CR- (CH3) 2

2-butylaminocarboxyethyl acrylate CH0 = CH 71 no2o

'1.4609

; oo-ch2-ch2-o-co-nh- (ch2) 3-3

2-Cyclohexylaminocarboxy-ethyl CH2 = CH 65.5 52-55

aCfylate COO-CH 2-CH2-0-OONH- ^ H ^

2-phenylaminocarboxyethyl acrylate CH ~ = CH 88.5 59

1 «r— \

COO-CH 2-CH 2-O-CO-NH-

633963

18th

2. Polymer Example 1 copolymer of the formula

4th

ch2-o-co-ch5

ch. c

«•

ch2-0-c0-ch5

CH - CH i i

CO CO

xo ^

CH "-

CH "-OH

8 2

C.

I.

CH2-0H

CH

t

CH-

i

COONa COONa of the copolymer in portions and heats the suspension to 65 ° C. After 4 hours, the product is filtered off with suction, washed until neutral and dried.

Yield: 485 parts by weight = 97.8% of theory; BAY h 5 2021.

Example 2 Copolymer of the formula

10th

430 parts by weight of l, 3-diacetoxy-2-methylene propane, 245 parts by weight of maleic anhydride and 15 parts by weight of tert-butyl peroctoate are dissolved in 1200 parts by volume of ethyl acetate. After stirring for 6 hours at 80 ° C., the viscous solution is allowed to cool and sprayed in 3000 parts by volume of benzene, the precipitated polymer is suctioned off and dried.

Yield: 655 parts by weight = 97% of theory. Softening point: 164-183 ° C;

tj rei: 1.08.

Saponification to the sodium salt of the polymeric carboxylic acid of the formula

4th

CH_-0-C0-NH-CH_ i * 3 CH "- C

i

CH2-0-CO-NH-CH5

CH0-CH

£ i

N

° ilj

180 parts by weight of sodium hydroxide are dissolved in 2000 parts by volume of methanol. Then you carry 540 parts by weight

210 parts by weight of N-vinylpyrrolidone and 90 parts by weight of 1,3-bis- (methyl-20 aminocarboxy-) 2-methylene propane are dissolved in 1000 parts by volume of benzene and heated to 80.degree. After adding 3 parts by weight of azodiisobutyro-nitrile, the mixture is stirred for 3 hours. During this time, the polymer precipitates, it is suctioned off, washed with benzene and dried.

25 Yield: 285 parts by weight = 95% of theory; BAY i 7433.

Softening point: 183-187 ° C il: 1.11 (1 g / 100 ml DMF at 20 ° C)

1.81 (5 g / 100 ml DMF)

so 2.41 (10 g / 100 ml DMF)

Example 3

Copolymer of the formula

CH - G-CO-NH-CH, 1 2 3

CH, - C

2 l

CH-O-CO-NH-CH

• <| H3

CH - C -

'i

"Ch coo-ch2-ch2-n ^

£

ch,

20 parts by weight of 1,3-bis (-methylaminocarboxy) -2-methylene propane and 20 parts by weight of dimethylaminoethyl methacrylate are dissolved in 200 parts by volume of water, and 0.8 parts by weight of azodiisobutyronitrile are added. The mixture is heated to 70-75 ° C. with stirring for 2 hours. The polymers in solution are isolated after cooling by precipitation in 1000 parts by volume of acetone. After suction and washing, it is dried in a vacuum at 50 ° C.

Yield: 35.2 parts by weight = 88% of theory. Softening point: 90-93 ° C.

Example 4

Polymer 1,3-bis (methylamino-carboxy) -2-methylene-55 propane of the formula

The homopolymer is dried using solvent. Yield: 83 parts by weight = 83% of theory. Softening point: 122-130 ° C.

Example 5

Copolymer of l, 3-diacetoxy-2-methylene propane and N-vinyl pyrrolidone

4th

CH, - C-2 I

CH "-0-CO-CH, I

CH2-0-CO-CH3

CH0-CH- '1

4th

-y— CH2 - C

ch ", - o-co-nh-ch, 1 * 5

CH? -0-C0-NH-CH5

100 parts by weight of 1,3-bis (methylamino-carboxy) -2-methylene propane are mixed with 2 parts by weight of di-tert-butyl peroxide and heated to 130-140 ° C. for 5 hours. Then the viscous polymer is purified by pouring and stirring in ethyl acetate. After decanting the

The polymer (BAY h 2014) is produced according to Example 2. It is a white hygroscopic powder with a 60 softening point of 152-160 ° C and a K value of 24. The polymer consists of 28% of 1,3-diacetoxy-2-methylene propane and 72% of N-vinylpyrrolidone, determined through N analysis.

The yield is 90%.

65

Example 6

Copolymer of 1,3-diacetoxy-2-methylene propane and vinyl acetate

19th

633 963

ch2-o-co-ch5 _ (lch2 - ç chj-oh j-

CH2-0-c0-chj o-co-ch ^

Analogously to Example 4, vinyl acetate and 1,3-yield 92%, t | are polymerized row: 1.61.

Diacetoxy-2-methylene propane in bulk. After 5 hours, the remaining monomers are stripped off in vacuo and the clear, highly viscous polymer is poured out. In example 7

At room temperature it solidifies into a brittle glass-like terpolymer made from styrene, maleic anhydride and

Product with a K value of 47.5. After saponification, the 1,3-diacetoxy-2-methylene propane polyol is water-soluble.

. ch2-o-co-ce3

- {- ch2-ch-ch - ch - ch2 - c

co co ch, -o-co-ch,

lyj xo / 3

The polymer 20 prepared as described in Example 2, Example 8

has a K value of 57, a softening point of 208-215 ° C, copolymer of 1,3-dipropioxy-2-methylene propane and is obtained in a 78% yield. After saponification to the acrylic acid Na salt of the polymeric carboxylic acid, the polymer is water-soluble.

ch2-o-co-ce2-ch5

ch2 - c ch2-ch ch2-o-co-ch2-ch5

cooh

A white powder, Example 9, is obtained in 78% yield

as prepared in Example 2, with a K value of 52 and a copolymer of 1,3-dipropioxy-2-methylene propane with a softening point of 176-184 ° C. and N-vinylpyrrolidone ch2-o-co-ch2-ch?

_ (_ oh2 - ç ch2- çh -) -

ch_-0-c0-ch -ch / itv

* d ■> n- »i x.

According to the procedure in Example 2, 30% by weight yield: 88%.

1,3-dipropioxy-2-methylene propane and 70% by weight N-vinyl

polymerized pyrrolidone. The polymer is a white hy- 45 Example 10

wholesale and water-soluble powder with an Er-copolymer of l, 3-dipropioxy-2-methylene propane softening point 156-162 ° C. and acrylic acid amide

4th

ce, -0-c0-ch - ch_

ch- - c ch, -ch

2 1 2 1

ch2-0-c0-ch2-ch5 c0-nh2

Polymerize 50 wt .-% l, 3-dipropioxy-2-methy softening point: 267-283 ° C.

lenpropane and 50% by weight acrylic acid amide as in Example 2

a water-soluble white powder example 11 is obtained

ver. copolymer of l, 3-dibenzoxy-2-methylene propane

Yield: 87%; 60 and N-vinyl pyrrolidone

CE,

r2-0-C0 ^ g>

-r— ch, - c ch - ch f

^ 2 1 nz \ 2 's ch -0-c0- / o)

\ _ /! -

633 963

20th

Analogously to Example 3, 30% by weight of l, 3-dibenzoxy-2-methylene propane and 70% by weight of N-vinylpyrrolidone are polymerized.

Yield: 95%

T | rei: 1.11

Softening point: 183-195 ° C.

Example 12

Copolymer of 1,3-dibenzoxy-2-methylene propane and acrylic acid

ch, - c i i

-O-OO ^ g)

CHj-O-CO- «»

ch - ch-2 |

c00h

50% by weight of l, 3-dibenzoxy-2-methylene propane and 50% by weight of acrylic acid are polymerized as described in Example 2.

Yield: 70%

K value: 52

Softening point: 164-170 ° C t | rei: 1.74.

Example 13

Copolymer of l, 3-dibenzoxy-2-methylene propane and acrylic acid amide k

-ch_ -

<! H2

c

I.

ch,

-o-co- ^)

(

-O-OO ^ Q)

ch "-ch-

i co-hh,

* 2 v 2

If 50% by weight of l, 3-dibenzoxy-2-methylene propane and 50% by weight of acrylic acid amide are polymerized analogously to Example 2, a white, water-soluble polymer is obtained in 75% yield with a softening point at 300 ° C.

Example 14

Copolymer of l, 3-bis (amino-carboxy) -2-methylene-5 propane and N-vinyl pyrrolidone k

10th

ch, -0-c0-hh, I 2 2

ch, - c

2 i ch ch, -ch c i

2-0-c0-hh2

o * L_J

The copolymer of 30 wt .-% l, 3-bis- (amino-carb-oxy) -2-methylene propane and 70 wt .-% N-vinylpyrrolidone 15 is prepared as described in Example 2.

Yield: 94%

K value: 25 T]: 1.20.

Example 15

2o copolymer of l, 3-bis (amino-carboxy) -2-methylene propane and maleic anhydride

4th

ch2-0-c0-nh2

ch, - c

2 |

ch2-0-c0-nh2

ch i

co

- ch-CO

If 50% by weight of l, 3-bis (aminocarboxy) -2-methylene propane and 50% by weight of maleic anhydride are copolymerized as in Example 30, a white powder is obtained in 60% yield, which is water soluble after saponification to the sodium salt of the polymeric carboxylic acid.

Example 16

35 copolymer of l, 3-bis (methylamino-carboxy) -2-methylene propane and vinyl acetate kr ch, - c

2 |

ch ,, - 0-c0-nh-ch_

l?

ch2-0-c0-nh-ch3

ch0-ch-I

o-co-ch.

50 wt .-% l, 3-bis- (methylamino-carboxy) -2-methylene- After saponification to the polyol, the polymer is water

propane and 50% by weight vinyl acetate become po-soluble in substance. v lymerized.

Yield 60% Example 17

Softening point: 76-80 ° C copolymer from 1,3-bis- (methylamino-carboxy) -2-

K value: 30 methylene propane and maleic anhydride il rei: 1.25 (1 g / 100 ml DMF 20 ° C) so ch2-o-co-nh-ch5

ch, - c ch - ch-

2 i | t ch, -o-co-nh-ch, co co d 5

When polymerizing 50 mol% l, 3-bis (methyl soap to the sodium salt of the polymeric carboxylic acid, it is

amino-carboxy) -2-methylene propane and 50 mol% maleic acid soluble.

Acid anhydride analogous to Example 2 is obtained in an Example 18

Loot of 87% the desired polymer (BAY h 2018) with 6o terpolymer made of styrene, maleic anhydride and a softening point of 131-147 ° C. According to Ver, 3-bis (methylaminocarboxy) -2-methylene propane

4th

4th

ch, -0-c0-hh-chx cb2 - £ -

2 l ch2-0-c0-nh-ch5

21st

633963

25 vol% styrene, 50 mol% maleic anhydride and after saponification to the sodium salt of the polymeric acid

25 mol% l, 3-bis- (methylamino-carboxy) -2-methylenpro- it is water-soluble.

pan are polymerized as in Example 2. Polymer Example 19

(BAY h 2020) has a K value of 30 and a softening copolymer made from 1,3-bis- (iso-propylamino-carboxy) -2-

point 195-230 ° C. The yield is 93%. s methylene propane and N-vinyl pyrrolidone ch2-0-c0-nh-ck- (ch5) 2

ch0 - c ch0-ch-

2, 2 i ch - 0-c0-ne-ch- (ch)

5 0 = 1_J

Analogously to Example 1, 30% by weight of 1,3-bis (iso-pro Example 20

pylamino-carboxy-2-methylene propane and 70 wt .-% N-15 copolymer from 1,3-bis (propylamino-carboxy) -2-vinylpyrrölidone polymerized. methylene propane and maleic anhydride

Yield: 94%

r | rei: 1.11.

ch, -o-co-nh-ch, -ch.-ch ..

/, 2 223

ch2 - c ch - ch — 4-

ch "-0-c0-nh-cho-cho-ch, co co

2 223 ^

As described in Example 2, 50 mol% of 1,3-bis- 25 After saponification to the sodium salt of the polymeric car- (propylamino-carboxy) -2-methylene propane and 50 mol% of acid, the polymer is water-soluble. Polymerized maleic anhydride.

Yield: 91% Example 21

Copolymer of l, 3-bis (cyclohexylamino-carboxy) -2 softening point: 148 ° C 30 methylene propane and maleic anhydride ch2-0-c0-nh- ^ jt)

- (- ce, - Ì ch - ch 4-

V 2 I / -s, I I S

ch2-0-c0-nh- ^ h ^ co ^ zq

50 mol% l, 3-bis (cyclohexylamino-carboxy) -2-methy- after saponification to the Na salt of the polymeric car-

Lenpropane and 50 mol% maleic anhydride are like water acid, the polymer is water-soluble.

polymerized as described in Example 1. 40

Yield: 62% Example 22

Copolymer of 1,3-bis (cyclohexylamino-carboxy) -2-11 rei. : 1.18 methylene propane and N-vinylpyrrolidone ch2-o-co-nh / F \

r_ch - c ch.-ch — v

^ 2 1 / —v * 1 y ch2-0-c0-nh- ^ hj) / n \

Analogously to Example 1, 30% by weight of 1,3-bis Example 23 are polymerized

(Cyclohexylamino-carboxy) -2-methylene propane and 70 wt. copolymer of 1,3-bis (phenylamino-carboxy) -2-me% N-vinylpyrrolidone. ethylene propane and N-vinyl pyrrolidone

Yield: 96%

ri rei .: 1.12. 55

çhj-o-co-sh-o)

X— ch. - c— ch, -ch — 4-

ch „-0-c0-kh- / q \

0si 1

30% by weight l, 3-bis- (phenylamino-carboxy) -2-methylene pro ri: 1.18.

pan and 70% by weight of N-vinylpyrrolidone are polymerized analogously to Example 2. The polymer is water soluble and has Example 24

has a K value of 23. Copolymer of 1,3-bis- (phenylamino-carboxy) -2-me-

Yield: 92% ethylene propane and maleic anhydride

633 963

22

ce2 -

CH2-0-C0-ÏÏH

c

ch2-0-c0-nh

50 mol% l, 3-bis (phenylamino-carboxy) -2-methylene propane and 50 mol% maleic anhydride are polymerized as described in Example 2.

Yield: 72%

Softening point: 118-121 ° C.

After saponification to the sodium salt of the polymeric carboxylic acid, the polymer is water-soluble.

Example 25 Copolymer of acrylic acid amide and carbamic acid allyl ester

-tCH2-CH-

CO-NH.

-CH - CH-CH.

4-

n

-O-CO-NH.

10th

15

ch - ch-

co do ^ o ^ •

50 mol% of acrylic acid and 50 mol% of 3,4-bis (methyl-aminocarboxy) -butene-1 are polymerized as described in Example 1.

Yield: 73%

Softening point: 197-200 ° C

Example 28

Copolymer of N-vinylpyrrolidone and 3,4-bis (methyl aminocarboxy) butene-1

20th

20.2 parts by weight of carbamic acid allyl ester and 14.2 parts by weight of acrylic acid amide are dissolved in 100 parts by weight of benzene. After adding 0.35 part by weight of azodi-isobutyronitrile, the mixture is heated to 80 ° C. and stirred for 6 hours. During this time the polymer precipitates, it is suctioned off, washed and dried.

Yield: (79% of theory)

Softening point: 270 ° C

Example 26

Copolymer of acrylic acid and 3-phenylaminocarboxypropen-1

■ 4 — CH -CH-

S

<fQ

-CH2-CH-

4th

n

CH-O-CO-NH-CH3 CH2-0-CO-NH-CH3

30th

If 50 mol% of 3,4-bis- (methylaminocarboxy) -butene-1 and 50 mol% of N-vinylpyrrolidone are polymerized analogously to Example 1, a white, water-soluble polymer is obtained in an 87% yield a softening point of 110-112 ° C.

T | rei: 1.07

Example 29

Copolymer of acrylic acid amide and 3,4-bis (butyl aminocarboxy) buten-l

CH - CH-

COOH

-CH - CH-CH-

^ r— \:

-O-CO-NH-v '\

f-CH ~ -CH-

CO-NH.

-ch - ch-

^ i n

Analogously to Example 1, 50 mol% of acrylic acid and 50 mol% of 3-phenylaminocarboxypropene-1 are polymerized. Yield: 85%

Softening point: 128-150 ° C t] re: 1.45

Example 27

Copolymer of acrylic acid amide and 3,4-bis (methyl aminocarboxy) buten-1

H

-f — CH ~ -CH-

-CH -.- CH-

n

CO-NH.

40

ch-o-co-nh-c.hq i 4 9

ch2-0-c0-nh-c4h9

CH-0-CO-NH-CH3 CH2-0-CO-NH-CH.

CH-,

50

The copolymer of 50 mol% of acrylic acid amide and 50 mol% of 3,4-bis (butyl-aminocarboxy) butene-1 is prepared as described in Example 1.

Yield: 66%

Softening point: 270-277 ° C

Example 30

Copolymer of 2-hydroxyethyl methacrylate and maleic anhydride

-fCH_-C- '»

coo-ch2-ch2-oh

Ö

CH-

-CH-

O

n

60 parts by weight of 2-hydroxyethyl methacrylate, 49 parts by weight of 60 maleic anhydride and 1 part by weight of tert-butyl perokate are dissolved in 500 parts by weight of ethyl acetate and heated to 80.degree. The polymer precipitates within 6 hours. It is suctioned off, washed with ethyl acetate and dried.

Yield: 92 parts by weight (84% of theory)

Saponification to the sodium salt of the polymeric carboxylic acid of the formula

CH, ■ j

■ {—ch - c-

coo-ch2-ch2-ch

CH

i

COONa

CH

COONa

40 parts by weight of sodium hydroxide are dissolved in 500 parts by volume of methanol. 100 parts by weight of the copolymer are then introduced in portions and the suspension is heated to 65.degree. After 4 hours, the product is filtered off with suction, washed until neutral and dried.

Example 31

Polymeric 3,4-bis (methylaminocarboxy) butene-1 of the formula

-f-c h2-ch) -

ch-o-co-nh-ch3 ch2-o-co-nh-ch3

100 parts by weight of 3,4-bis- (methylaminocarboxy) -butene-1 are mixed with 2 parts by weight of di-tert-butyl peroxide and heated to 130-140 ° C. for 5 hours. Then the viscous polymer is poured into it and stirred into vinegar.

633963

acid ethyl ester cleaned. After decanting off the solvent, the homopolymer is dried.

Yield: 86 parts by weight - 86% of theory

Example 32

Copolymer of N-vinylpyrrolidone and 3-methyl-aminocarboxypropen-1

—Fch2-ch ch2-ch h-

o x n. ch., - o-co-nh-ch,

Tj

70 parts by weight of vinylpyrrolidone and 30 parts by weight of 3-methylaminocarboxypropen-1 are dissolved in 250 parts by volume of benzene and heated to 80.degree. After adding 1 part by weight of azodiisobutyronitrile, the mixture is stirred for 5 hours, during which the polymer precipitates, and is filtered off with suction and dried.

Yield: 93 parts by weight = 93% of theory

23

5

10th

15

s

Claims (6)

633 963 2nd PATENT CLAIMS 1. Antituraoral agents, characterized in that they contain at least one water-soluble homo- or copolymer which contains unsaturated mono- or poly-hydroxy compounds or their esters or urethanes. 2. Antitumor agent according to claim 1, characterized by a content of at least one water-soluble compound of the general formulas ch - 0-r t ' - <- ch - c- 'i ch2-0-r (Y) (z) (I) ^ » ch2-o-r w- - (z) - (ii) ch2-c » ch-o-r ch2-o-r ch2-c- coochch2-o-r « b • (y> - (iii) (iv) bliss R is hydrogen, - <jj! -Alkyl, -Ç-cycloalkyl, -Ç-aryl- O O O -C-NH2) -C-NH-alkyl, -C-NH-cycloalkyl or -C-NH- II II J! ! [ o o o o Aryl, A is hydrogen or methyl B is hydrogen or methyl Y and Z units of monomers copolymerizable with the unsaturated mono- or polyhydroxy compounds or their esters or urethanes, P = 10 to 100 mol% q = 0 to 90 mol% and r = 0 to 90 mol% mean. 3. Antitumor agents according to claims 1 and 2, characterized by a content of at least one water-soluble compound of the general formulas I to IV in claim 2, wherein Y and Z units of maleic acid, maleic anhydride, fumaric acid, acrylic acid, optionally in salt form, acrylamide, Fumaric or maleic acid halamides, optionally in salt form, styrene, hydroxyalkyl (methyl) acrylate, sulfoalkyl (meth) acrylate, vinyl pyrrolidone, vinyl caprolactam, vinyl pyridine, vinyl imidazole, allyl hydantoin or methacrylic acid salicylate. 4. Antitumor agent according to claim 1, characterized by a content of at least one water-soluble copolymer containing 30 parts by weight of 1,3-bis Contains 40 (methyl) aminocarboxy-) 2-methylene propane. 5. Antitumor agent according to claim 1, characterized by a content of the water-soluble copolymer of 30 parts by weight of l, 3-bis (methylamino-carboxy) 2-methylene propane and 70 parts by weight of N-vinyl 45 pyrrolidone. 6. A process for the preparation of an antitumor agent according to claim 1, characterized in that at least one water-soluble homopolymer or copolymer, the unsaturated mono- or polyhydroxy compound Fertilize 50 or contains their esters or urethanes incorporated, dissolves in a physiological saline solution. 55