AGENTS HAVING A TUMOUR-INHIBITING ACTION AND THEIR USE

AGENTS ANTI-TUMORAUX ET UTILISATION

English Abstract

Agents having a tumour-inhibiting action and their use
ABSTRACT OF THE DISCLOSURE
* * * *
The invention relates to pharmaceutical compositions
containing, as an active ingredient, an effective amount
of a non-ionic water-soluble vinylic or acrylic polymer
containing carboxamide groups derived from monomers of
formula (I) as defined in the specification. The compositions
are useful as anti-tumour agents. Also included in the
invention are methods for combatting diseases caused by
tumours.
Le A 20 391-CA

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition containing as an active ingredient a non-
ionic water-soluble vinylic or acrylic polymer containing carboxamide groups and
having a molecular weight ?n of 300 to 50,000, in the form of a sterile and/or
physiologically isotonic aqueous solution or in the form of a tablet.
2. A composition according to claim 1, in which the water-soluble polymer
is synthesized from one or more monomers of the general formula
<IMG> I
in which X denotes a hydrogen atom or a C1 to C4 alkyl group, and R1 and R2 are
identical or different and denote a hydrogen atom or an alkyl, cycloalkyl, aryl
or heterocyclic group having up to 10 carbon atoms, or R1 + R2 denotes an
alkylene group having 3 to 5 carbon atoms or -CH2-CH2-O-CH2-CH2-.
3. A composition according to claim 2, in which X denotes a hydrogen
atom or a methyl group and the sum of the carbon atoms in the radicals R1 and
R2 is less than or equal to 11.
4. A composition according to claim 1, in which the water-soluble polymer
is synthesized from one or more monomers of the general formula
<IMG> II
in which R1 and R2 are identical or different and denote a hydrogen atom
14

or an alkyl, cycloalkyl, aryl or heterocyclic group having up
to 10 carbon atoms, or
R? + R? denotes an alkylene group having 3 to 5 carbon atoms.
5. A composition according to claim 4, in which R? and R? independ-
ently denote a hydrogen atom or a C1 to C4 alkyl group.
6. A composition according to claim 1, in which the water-soluble
polymer is a copolymer of monomers of the formulae (I)
<IMG> (I)
in which
X denotes a hydrogen atom or a C1 to C4 alkyl group, and
R1 and R2 are identical or different and denote a hydrogen
atom or an alkyl, cycloalkyl, aryl or heterocyclic group having
up to 10 carbon atoms, or R1 + R2 denotes an alkylene group
having 3 to 5 carbon atoms or -CH2-CH2-O-CH2-CH2-.
and formula (II)
<IMG> (II)
in which
R? and R? are identical or different and denote a hydrogen atom
or an alkyl, cycloalkyl, aryl or heterocyclic group having up
to 10 carbon atoms, or
R? + R? denotes an alkylene group having 3 to 5 carbon atoms.
7. A composition according to claim 6 wherein in formula I X denotes
a hydrogen atom or a methyl group and the sum of the carbon atoms in the

radicals R1 and R2 is less than or equal to 11.
8. A composition according to claim 7 wherein in formula II R? and
R? independently denote a hydrogen atom or a C1 to C4 alkyl group.
9. A composition according to claim 1, 2 or 3, in which the water-
soluble polymer is formed from 7 to 500 of the monomer units.
10. A composition according to claim 4, 5 or 6, in which the water
soluble polymer is formed from 7 to 500 of the monomer units.
11. A composition according to claim 7 or 8, in which the water-
soluble polymer is formed from 7 to 500 of the monomer units.
12. A composition according to claim 1, in which the water-soluble
polymer is a copolymer of 0 to 99 mol% of monomers of the formula (I)
<IMG> (I)
in which
X denotes a hydrogen atom or a C1 to C4 alkyl group, and
R1 and R2 are identical or different and denote a hydrogen atom
or an alkyl, cycloalkyl, aryl or heterocyclic group having
up to 10 carbon atoms, or R1 + R2 denotes an alkylene group
having 3 to 5 carbon atoms or -CH2-CH2-O-CH2-CH2-.
0 to 99 mol% of monomers of the formula (II)
(II)
<IMG>
in which
R? and R? are identical or different and denote a hydrogen atom
16

or an alkyl, cycloalkyl, aryl or heterocyclic group having up
to 10 carbon atoms, or
R? + R? denotes an alkylene group having 3 to 5 carbon atoms.
and 1 to 70 mol% of one or more other non-ionic vinylic or acrylic monomers.
13. A composition according to claim 1, 2 or 3, in which the water-
soluble polymer has a molecular weight ?n below 25,000.
14. A composition according to claim 4, 5 or 6, in which the water-
soluble polymer has a molecular weight ?n below 25,000.
15. A composition according to claim 7 or 8, in which the water-
soluble polymer has a molecular weight ?n below 25,000.
16. A composition according to claim 1 wherein the active ingredient
is a polymer of acrylamide having a viscosity [n] of 0.064 (determined at
25°C in 0.9% strength aqueous NaCI solution).
17. A composition according to claim 1 wherein the active ingredient
is a polymer of methacrylamide having a viscosity[n]of 0.082 (determined at
25°C in 0.9% strength aqueous NaClsolution).
18. A composition according to claim 1 wherein the active ingredient
is a copolymer of acrylamide and N-vinylpyrrolidone having a viscosity [n]
of 0.042 (determined at 25JC in 0.9% strength aqueous NaClsolution).
19. A composition according to claim 1 wherein the active ingredient
is a copolymer of acrylamide and N-vinylpyrrolidone having a viscosity [n]
of 0.049 (determined at 25°C in 0.9% strength aqueous NaCl solution).
20. A composition according to claim 1 wherein the active ingredient
17

is a polymer of N-vinylacetamide having a viscosity [n] of 0.12 (dotermined
at 25°C in 0.9% strength aqueous NaCl solution).
21. A composition according to claim 1 wherein the active ingredient
is a polymer of N-vinyl-N-methylacetamide having a viscosity [n] of 0.21
(determined at 25°C in 0.9% strength aqueous NaCl solution).
22. A composition according to claim 1 wherein the active ingredient
is a polymer of N-vinylpyrrolidone having a molecular weight ?n of 3,400
(determined by vapour pressure osmometry in DMF) and a viscosity [n] of 0.051
(determined at 25°C in 0.9% strength aqueous NaCl solution).
18

Description

77~
~ T~lpe II ~Pha)~
The present ir~v~ntion relates ta the use as agents
having a tumour-inhibiting action of' non-ionic water-
soluble polymers containing carboxamide groups, which are in
themselves known.
It has already been disclosed that complex CuII and
CoII salts of ethylene/maleic acid copolymers are active
against Walker's sarcoma Csee J. Med. Chem., 12 (1969),
1,180~.
Furthermore~ polycations of various types, for example
1Q polyamidoamines, poly-N-morpholinoethylacrylamide and N-oxide
polymers, have been tested for inhibition of'the formation of
metastases, with the result ~that only the dissemination of
tumour cells, but not the growth of metastases in situ or
metastases in a lymph node, could be influenced [see J. Med.
Chem., 16, (1g73), 496].
The activity of polymers' with carboxyl groups against
180 sarcoma, as a function'of the molecular weight, the
charge density and also the metal~binding capacity of the
carboxyl gr~oups, has also been described ~see Dissertation
Abstr- Intern. B 33 (1973)5 5,745].
Polyanions, for example poly-(ammonium acrylate),
acrylic acid/acrylamide copolymers and also ethylene/maleic
anhydride copolymers, are said to hav~, in connection with
their tumour-inhibiting action, a heparin ~-like effect and
also a virus inhibition, and moreover to increase the
immunoreactions ~see J. Med. Chem., 17, (1g74), 1,335].
It is apparent from all this work that the tumour-
inhibiting action of the polymers investigated hitherto
against the experimental tumours used frequently only lies
at the lower limit of significance and, in a number of cases,
is restricted to prophylactic or adjuvant effects only.
Le A 20 391
; ~ . .
. .

'~L77~
Disadvanta:geousl~, it is moreov~r apparent that the invest-
igation~ citEd were ca~ried out in many cases on allogenic
mouse tumours having a tendency towards spontaneous regress-
ion, and not systematically and under experimental arranqe-
ments relevant to clinical conditions. Generally, thereis a lack of data on ~he toxici.ty of the preparations~ although
the administratio~ of ~igh dosos of substances having a mole-
cular weight of more than 30,ûOO suggests inadequate elimin-
ation, or sto:rage in the tissues.
lQ Moreove.r, a certai~ tumour-inhibiting action of emulsi-
fiers which contain incorporated polyethylene oxide chains
has been disclosed. Thus, polyoxyethyleneated sorbitan
monooleate ("T.ween" 80 - Trade Mark) has been used for
immunisatiOn agai~st ~yperdiploid Ehrlic~.'s tumour ~see
Experien-tia,.29 (1973), 71~]..
A block copol.ymer of polypropyIene oxide and poly-
ethylene oxide ("Pluronic"F 68 - Trade Mark) has proved to
be active against the onset of metastases of Walker's 256
Ascites tumour, probably by influencing the blood coagul-
ability [see Cancer, 29 (1972)~ 171~. As is known, these
preparations are highly active emulsifiers and for this
reason are not very well tolerated, in particular on
parenteral administration.
Likewise,. agents having a tumour-inhibiting action have
been described, which are characterised in.that they contain
at least one water-soluble homopolymer or copolymer which
contains 1,3-dihydroxy-2-methylene-propane and/or deriva-
tives therebf [see DOS (German Published Specification)
2,705,189]. Similar preparations with a similar action are
water-soluble homopolymers or copolymers which contain 3,4-
dihydroxybut-1-ene or hydroxyalkyl (meth)-acrylates or deriva-
tives thereof, or also derivatives of allyl alcohol, in poly-
merised or copolymerised form [s.ee DOS (German Published
Specification) 2,740,082].
B.S.Michaels et al. Csee Nature,.21:Z,. (1966), 101] hav~
Le A 20 391

-
- ; ~
~1'774~4
described the virus-inhibiting action of'polyvinylpyrral-
idone (PVP). In experiments carried out in vitro3 PVP
concentrations ~ 10 mg/ml distinctly inhibited plaque
formation in the case of herpes simplex virus a~d vaccinia
virus, whereas a con'centration of 1 mg/ml had no action.
In experime~ts carried out _ Vi.V~o -OQ 3-day-old' chicks
[see ~.S.Michaels et al., Proc. Amer. Ass. Cancer Res., 8,
April (1g67), 45], an inhibition of the virus-induced
tumour formation ~as been observed in the case of the simul-
taneous administration of Rous sarcoma virus (RSV)' and PVP.
Pretreatment of the chicks had only a small effect, whereas
PVP administered 6 hours after the virus infection was still
acti~e.
~ he'se results in no way suggest that PVP7 even in very
small doses, possesses significant inhibiti~ng ac~ions against
non virus-induced tumours both in a prophylactic capacity
(6 days before the tumour transplantation (TT)') and also in a
curative capacity (2 days a~ter the TT)'.
W. Regelson-et al. ~see Nature, 186, (1960), 778-780]
2Q have investigated the tumour-inhibiting action of synthetic
polyelectrolytes such as polyacrylic acid, polymetha~rylic
acid and hydrolysed or aminolysed ethylene/maleic anhydride
copolymers. By comparing the actions of the dicarboxylic
acid form, the amido-carboxylic acid form and the diamido
form of ethylene/maleic anhydride copolymers, they found
that at least one ionisable carboxyl group is necessary for
a significant tumour inhibition. Experiments carried out by
these authors with polyacrylamidesin high doses (800 mg/kg,
MW 60-70',000 and 400 mg/kg, MW 120,000) showed a negative
~û tumour-inhibiting action or a non-significant, very weak
positive action.
It has now been found, surprisingly, that non-ionic
water-soluble polymers co~taining carboxamide groups also
possess significa~t tumour-inhibiting actions against solid
tumours in a broad dosage range of 0.5-50nmg/kg, preferabIy
Le A 20 391'

7~4~D~
2.5 to 250 mg/kg, under experimental arrangements and methods of administration
relevant to clinical conditions.
The acute toxicities of the substances are low (LD50, administered
intravenously: >2,500 mg/kg), so that the substances have an unusually large
therapeutic range.
According to the present invention we therefore provide a pharmaceuti-
cal composition containing as an active ingredient a non-ionic (as herein defin-
ed) water-soluble vinylic or acrylic polymer containing carboxamide groups and
having a molecular weight M of 300 to 50,000, in the form of a sterile and~or
physiologically isotonic aqueous solution. Furthermore, peroral administration
is possible.
"Non-ionic" polymers are to be understood as meaning polymers which
do not dissociate electrolytically when used under physiological conditions,
that is to say which do not have amino, carboxyl or sulphonic acid groups in
particular.
Preferred polymers containing carboxamide groups which may be used
according to the invention are those synthesized from one or more monomers of
the general formula
X / R
CH = C - CON
R2
in which X denotes a hydrogen atom or a Cl to C4 alkyl group, particularly
preferably a hydrogen atom or a methyl group, and Rl and R2 are identical or
different and denote a hydrogen atom or an alkyl, cycloalkyl, aryl or hetero-
cyclic group having up to 10 carbon atoms, the sum of the carbon atoms in the
radicals Rl and R2 preferably being ~11, or Rl -~ R2 denotes an alkylene group
having 3 to 5 carbon atoms or -CH2-CH2-0-CH2-CH2-, or from one or more monomers
of the general formula
.:
. ~ .

~ ~ 779~a4
CH - CH - N~ 2 (II)
2 ~ C0-R
in which
R1-and R2 are identical or dif'ferent and
denote a hydragen atom or an alkyl, cyclo-
alkyl, aryl or-heterocyclic group having up
to 10 carbon atoms, preferably a hydragen
atom or a C1to C4 alkyl group, or
R1 + R2 denotes an alkylene group having 3
to 5 carbo~ a~oms~
In both cases, pol'ymers formed from 7 to 500 monomer units
are-preferred.
Starting from the cor~esponding monomers, the polymers
can be prepared by known methods,-for example by free-
radical polymerisation. In this process, the polymerisation
can be oarried out in a solvent which dissolves the monomer
and the poIymer (solution polymerisation), in a solvent
which only dissolves the monomer (precipitation polymeris-
ation), or also without a solvent (bulk polymerisation).
The polymerisation processes which are preferably
chosen are those in which products having a relatively
narrow molecular weight distribution are obtained. The un-
reacted monomer constituents should be removed from the
products because'they are usually more toxic than the poly-
mers.
Thc following monomers having the general formula (I)'
may be especially mentioned: acrylamide, metharrylamide, N-
methylacrylamide,'N-ethylacrylamide, N,N-dimethylacrylamide,
N-isoprapylacrylamide and N-acryloylmorpholine.
The following monomers having the general formula (II)
may be mentioned: N-vinylformamide, N-vi~nylacetamide, N-
vinylpropionamide, N-vinylbutyramide, N-vinyl-N-methylaceta-
mide, N-vinyl-N-ethylacetamide, N-vinylpyrrolidone, N-vinyl-
piperidone and N-vinylcaprolactam.
' '
Le A 20 391'

7~
The copol'ymeri'sation of'two 'or''more of the above-
mentioned mon-om~ers also leads to polymers to be used accord-
ing to the inventio~. Copolymerisation makes it possible,
for example, to ac~.ie~e the desired improved solubility of
the polymers in water.
It is moreover possible, if desired, also ta copolymer-
ise with 0 to 99 molO of monomers of formula (I) and 0 to 99
molO of monomers of formula (II), 1 to 70 moIO of one or more
other non-ionic vinylic or acrylic monomers, such as acrylo-
10. nitrile, esters of acrylic acid or methacrylic acid with.saturated monoalcohols having 1.to 8 carbon atoms, vinyl
esters of aliphatic carboxylic acids having 1 to 4 carbon
atoms, vinyl ethe'rs wi~h alk'yl radicals havi.ng 1 to 8 carkon
atom's, vinyl halides, such as vinyl chloride and vinylidene
15. chloride, and also di~s~ers of'malqic acid and fu~laric acid
with saturated aliphatic monoalcohols~ together with one or
more of the monomers containing carboxamide groups, the
amount of the comonomer being limited by the fact that the
polymer formed must be soluble in physiologically isotonic
sodium chloride solution, at 20 to 40C. to give solutions of
at least 0.56 strength by weight.
Preferably, the polymerisation is started by means of
initiators which form free radicals, such as aliphatic azo
compounds, diacyl peroxides, or percarboxylic acid esters or
percarbonic acid esters. In this process, the molecular
weight of the polymers formed can be influenced by various
known measures. Thus, the use of increasing amounts of
initiator gives polymers having a decreasing molecular
weight. A further possibility of reducing the molecular
weight consists in adding molecular weight regulators, such
as mercaptans, or in:using specific solve.nts, such as
isoprapanol.
The polymer-s cnn.taining carboxamide groups which are ta
be used acc.ording to the invention have. ave.rage molecular
weights Mn of 300 to 50,000. Polymers having molecular
- Le:A 20.391 :

- 7 -
wei.ghts belo'w 25,000 are'pre'ferr'e'd 'becau'se these can be
expected: to be eliminated through the kidneys.
In addition to exceptionally low toxicity, the agents
acc~rding to the inven.tion-have a strong tumour-inhibiti~ng
5 action against tumours in animals and hu'mans and are there-
fore intended for use in combating diseases caused by
tumours.
As stated above, the invention also relates ta the use
in human and Yeterinary medicine as anti-tumorial agents
1n f the compounds of the invention.
This invention further provides a method of combating
(including prevention, relief and cure of) the above-
mentiOned diseases in human and non-human animals, which
comprises administering to the animals a compound of the
invention in admixture with a diluent. For p.arenteral
administration, solutions should be sterile and, if appra-
priate, blood-isotonic.
' It-is envisaged that these active compounds will be
administered parenterally (for example intramuscularly,
intraperitaneally, subcutaneously and intravenously)_
systemically or locally~. preferably intraperitoneally,
intravenously or intramuscularly. Preferred pharmaceutical
compositions and medicaments are therefore those adapted for
administration such as intraperitoneal, intravenous or
intramuscular administration. Administration in the method
of the invention is preferably intraperitoneal, intravenous
or intramuscular administration. Furthermore, peroral admi-
' nistration is possible.
In general it has proved advantageous to administeramounts of from û.5 mg to 500 mg/k'g, preferably 5 mg ta 250
mg/kg, of body weight per day to achieve. ef'fective results.
Nevertheless, it can at times be necessary ta deviate from
those dosage~rates, and in particular ta do so as a functi~on
of the nature and body weight of the human or animal subject !
to be treated, the individual reaction of this subject ta
the treatment, t~e type of formula'tion in which the active~.
ingredient is administered and the mode in which the admin-
. . : . . . ~
Le A 2a 391

~774~4
- 8 -
istrati:on is carr`ied ou:t, and the point in the progress of
the disease or interval at which it is to be administered.
Thus it-m.ay in some cases suffice t~ use less than the abovel-
mentioned minimum dosage rate, whilst in other cases the
upper limit mentioned must be exceeded to achieve the
desired results.- Where larger amounts are administer.ed it:
can be advisable to divi;de these into seve.ral individual
administrations over the course of the day.
The tumour-inhibiting compositions according ta the
invention are prepared by dissolvi:ng the polymers containing
carboxamide graups in physiological sodium chloride solution
.. . . .. .. . . . .. ... .. .....
or by the manufacture of tablet in an usual manner. ~-
The agents according to the invention were tested in the
following manner against mouse carcinoma E0 771 on C 57 BL/6 mice:
Animal strain: C 57 BL~6. mice, inbred (SPF)
15: Methods: .Maintaining thë .tumor_strain: 14 - 20 days
- after- the last transplantation, sub-
cutaneous inoculation of a suspension
of cells of carcinoma E0 771 in 0.5 ml
of 0.9O phosphate-buffered NaCl solution
(PBS) into C 57 BL/6 mice.
.Preparation..o~..screening..tests:.; Same
process as in maintaining the strain of
the tumour, but subcutaneous inoculation
, of a suspension of a 5 x 104 tumour cells
in 0.5 ml of PBS.
.Treatment:, Single intramuscular injection
of the required solutions of the substance 6
days prior to or 2 days after the tumor
transplantation.
Duration.,of. exper,imen.t~s: l8- 22 days aFter
the tumour transplantati~on. Thereafter,
sacrificing oF the animals, prep.arati;on
and weighing of the subcutaneous tumours.
Le A 20 391

9 11~79~
Ev:~Lu'ati.bn para'meters: Inhibition,of the
tumour growth by determination of the
average tumour wei:ght of contr~l animals
and groups of treated animals and cal-
culation of the tumour weight (TW) index
according to the formula:
0 tumour weight of the
groups of treated
animals
1~ TW index~
0 tumour weight of the
control group
Assessment.~,f,.the,test,,result,s,, TW index:
-
0.8:- 0.6 = marginal activity;
lS ~- 0~6'- 0.4 = moderate activity; 0.4 - 0.0 _
good activity.
Table 1: Test results against carcinoma E0 771 after a single
intramuscular administration each.
Polymer of Dose Day of ' Tumour ~eight~
20 Example No. mg/kg treatment- index
,. ... ... ..... .. ... .
1', 2.5 - 6 0.21
2.5 ~ 2 , 0.28
2 2.5 - 6 0.22
250 ~ 2 0.. 55
3 10 - 6 0.32
~ 2 0.28
4 250 - 6 0.33
250 + 2' 0.53
, lO - 6 0,51
+ 2 0,68
6 lO - 6 0,53
~ 2 0,51
.. . .. .. .. . . .. .. . . .
7 10 - 6 0.26
; 2.5 ~ 2 0.40
Day of treatmen.t: -- 6 = 6 days. prior to tumor. transplant-
.' ation
+ 2'= 2'days after tumou~ tran.splant-
ation
. .
Le A Z0 391' F
. ~ ' "~,
- . ~ .

7~
-- 10 --
The tumour weight indices of the preparations listed in
Table 1 show that the substances a-t various doses and on
various days of treatment are capable of inducing significant
tumour-inhibiting activity (both after prophylactic as well
as curative treatment) against the standard tumor model
carcinoma E0 771 in mice.
The foll'owing Example's ill'ustrate the production of the:
polymers used in compositions of the present invention.
Example 1.
10. 400 ml of distilled isopropyl alcohol were initially
introduced into the apparatus, the latter was evacuated ta
100 mbars and filled with nitrogen 3 times and the solve.nt
initi-ally intro'duced was hea~ed ta the boil. 100 9 of
acrylamide and 1 9 of dilauroyl peroxide were dissolve.d in
1S .600 ml of isopropanol. The monomer solution was deox'ygenate~d
and added dropwise ta the stirred boiling sol'vent in th.e
course of 3 hours, nitrogen being passed over. The mixture
was subsequently stirred for 3 hours under reflux. The poly-
mer powder was filtered off, extracted by boiling wit~ 2 x 1'
litre of acetane, filtered off again and dried ta constant~
weight at 60C under reduced pressure. This yielded 95 9 of
polymer powder. [~ ] - 0.064 (determined at 25C in 0.9
strength aqueous NaCi solution).
' Example.2
400 ml of distilled ethyl ace.tate were initiall'y intro-
duced inta the apparatus. The latter was evacuated to 100
mbars and filled with nitragen 3 times and the solvent
initially introduced was heated ta the boil.
80 9 of methacrylamide and 1Q g of diethyl azoisobutyr-
ate were dissolve.d in 800 ml of`dis~illed'ethyl acetate. Th'e
monomer solution was deoxygenated and added dropwise to the
stirred boiling solve.nt in the course of 3 hours, nitrog0n
being passed ove.r. The mixture was subsequently: stirred for-
3 hours under reflux. The polymer was filtered off,
extracted by boiling with 2 x 1'litre oF acetone, filte'red
Le A 20 391

L774(~
- 11' :-
of'f again and dried at-60'C _ v'ac'u'a'.',
Yield': 66 9 of'pol'ymer
[~ ] = 0.082 (determined at 25~C in 0.9O strengt~ aqueous
NaCl solution).
Example 3'
1,-4ûO ml of distilled isopropyl alcohol were initially
introduced into the apparatus, as described in Example 2,
deoxygenated and heated ta the boil. 70 9 of'acrylamide,
30 9 of freshly distilled N-vinylpyrroli'done and 1 9 of di-
lauro-yl peroxide were dissolved in 600 ml of'distill'ed
isopropyl alcohol. The monomer soluti~on was deoxygenated
and uniformly added dropwise to the stirred boiling solvent~
in the course of 3 hours, nitrogen being passed over. The
mixture' was subsequently stirred for 3 hours under reflux and
the polymer was filtered off, washe'd thoroughly several
times with acetone and dried at 60C in vacuo.
Yield : 84 9
c7 ] = 0.042 (determined at 25C in 0.9O strength aqueous
NaCl solution).
Example 4
Analogously to- Example 3, a solution of 50 9 of acryl-
amide, 50 9 of N-vinylpyrrolidone and 1 9 of lauroyl peroxide
in 600 mI of isoprapyl alcohol was subjected to polymer-
isation.
Yield: 79 9
C~ ] = 0.049 (determined at 25C in 0.9~strength aque-ous
NaCi solution)~ ~
Example-5
50 9 of N-v-inylacetamide and 5 9 of azoisobutyrodi-
nitrile were dissolved in 300 ml of isobutyl alcohol. The
solution was carefully deoxygenated and heated at the boil
for 3 hours under nitrogen. The pol'ymer solu,tion was then
concentrated _:,vacu_ to about ,2ao ml 'and introduced into
2.5 li`tres of acetcne, whils't stirring. The polymer which
had precipitated out was washed tho'roughly with~ acetone and
dried in vacuo.
Le A 20 391'

~77~
.- 1Z
Yiel:d`: 27 9
[~ ] = 0.1Z ~d.eter:mined at 25C in 0.9~ strength aqueous
NaCl'solution).
Example -6
5G0 ml of'n-heptane were initiall'y'introduced into the
apparatus, as described in- Example'1,: deoxygenated and heate~d
ta 95C, whilst stirring. An oxygen-fre'e mixture-of' 95 g of.
N-vinyl-N-methyl-'acetamide, 5 g of diet~yl 'azoisobutyrate
and 150 ml of n-heptane was uniformly ad'ded dropwise in the
course of 2.5 hours, with the exclusion of oxygen. Th'e
reaction mixture was subsequently stirred for 2 hours at 95C
and coole'd to: room temperature and the polymer whichhad preci-
pitated. ou't~was filt'ered of'f, washed t~oroughly with- n-heptane
and dried.
1S. Y'ie~.d: 85.3 g
[~ ~ 0.21'(dete~mined at!25C in 0 9 O strength aqueous
NaCl solution).
Example:7
200 ml of'distilled isobutyl alcohol were initially
intraduced into the apparatus. The apparatus was evacuate~d
to 100 mbars and filled with nitrogen 3 times and the solvè.nt~
initially introduced was heated ta the boil. 300 g of freshly
distilled N-vinylpyrroli'done and 7.5 g of diethyl azoisobutyi-
rate were made up ta 1~200 ml with isobutanol. The monomer
solution was deoxygenated and uniformly ad~ed dropwise with 400 ml/
hour to the stirred boiling solvent, nitrogen being passed over.
The mixture was subsequently sti~rred for 2 hours
under reflux. 3 litres of n-butyl 'acetate were then added
to the batch.and 3 li'tres of solvent mixture were distill'ed
off at 300 t~ 400 mbars. After cooling to room temperature~:
the supernat~nt solve.nt was decanted. The polymer was
further'extracted wit~ 2'x 2 litres of but~l 'aceta~te for 2'
hours at 1Z0C and the'extraction agent was decanted after
cooli'ng. Solv'ent residues were then removed from ~'h'e poly-
mer. _ vacuo.`at 1Z0C on a rotary evaporator .and the polymer
Le A 20 391'

~7~0~
,, . - 13:_
was me~ha~icall'y' comminuted.
Yield': 173 9 of'polymer
Molecular weight Mn = 3~400 (determined by vapour~pressure
osmomet~-y in DMF).
/n7 = 0,051 (determined at 25C in 0,9 O strength
aqueous NaCl solution).
` ' , . : ,