AGENTS ANTI-TUMORAUX ET UTILISATION

AGENTS HAVING A TUMOUR-INHIBITING ACTION AND THEIR USE

Abrégé anglais

Agents having a tumour-inhibiting action and their use
Abstract of the Disclosure
The invention relates to pharmaceutical
compositions containing, as an active ingredient,
a water-soluble addition product of a polyether diol
and a diisocyanate. The compounds are indicated to
be useful as anti-tumour agents. Also included in
the invention is the use of said compositions as
anti-tumour agents.
-26-

Revendications

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
water-soluble addition product of a polyetherdiol and a diisocyanate having a
molecular weight in the range from 1,000 to 30,000, in the form of a sterile
and/or physiologically isotonic aqueous solution or in the form of tablets.
2. A composition according to claim 1, in which the active ingredient is
a water-soluble oligo-urethane or polyurethane of the general formula
<IMG>
in which Q denotes a polyether radical which optionally contains ionic groups,
the groups B are identical or different and denote a hydrogen atom or an
aliphatic, alicyclic or aromatic radical with up to 8 carbon atoms or a X-CO-
group in which X denotes a hydrogen atom or an aliphatic, alicyclic or aromatic
radical with up to 7 carbon atomsi or a Y-O-CO- group, in which Y denotes an
aliphatic, cycloaliphatic or aromatic radical with up to 7 carbon atoms, or a
Z-NH-CO- group, in which Z denotes a hydrogen atom or an aliphatic, cycloali-
phatic or aromatic radical with up to 7 carbon atoms, R denotes a bivalent
radical of a diisocyanate, and m denotes a number from 1 to 30.
3. A composition according to claim 2, in which Q denotes a radical of
the general formula
<IMG>
in which A denotes hydrogen or methyl in random distribution and n denotes a
number from 5 to 500.
4. A composition according to claim 3, in which n is a number from 8
t0 300.

5. A composition according to claim 2, 3 or 4, in which the groups B are
identical or different and denote a hydrogen atom, a C1 to C4 alkyl group, a
X-CO- group (in which X denotes a hydrogen atom or a C1 to C3 alkyl group), a
Y-O-CO- group (in which Y denotes a C1 to C4 alkyl group) or a Z-NH-CO- group
(in which Z denotes a hydrogen atom or a C1 to C4 alkyl group).
6. A composition according to claim 1, in which the active ingredient is
a water-soluble polyaddition product of a polyethylene glycol and a diisocyanate,
of the general formula
<IMG>
in which R denotes a bivalent radical of a diisocyanate, m denotes a number
from 1 to 30 and n denotes a number from 5 to 500.
7. A composition according to claim 2, 3 or 4 in which R denotes a
bivalent radical of the diisocyanate which is derived from hexamethylene
diisocyanate.
8. A composition according to claim 2, 3 or 4, in which the groups B are
identical or different and denote a hydrogen atom, a C1 to C4 alkyl group, a
X-CO- group (in which X denotes a hydrogen atom or a C1 to C3 alkyl group), a
Y-O-CO- group (in which Y denotes a C1 to C4 alkyl group) or a Z-NH-CO- group
tin which Z denotes a hydrogen atom or a C1 to C4 alkyl group), and in which
R denotes a bivalent radical of the diisocyanate which is derived from hexa-
methylene diisocyanate.
9. A composition according to claim 6 in which R denotes a bivalent
radical of the diisocyanate which is derived from hexamethylene diisocyanate.
10. A composition according to claim 2, 3 or 4, in which R denotes a
bivalent radical of the diisocyanate which is derived from isophorone diiso-
cyanate.
21

11. A composition according to claim 2, 3 or 4, in which the groups B are
identical or different and denote a hydrogen atom, a C1 to C4 alkyl group, a
X-CO- group (in which X denotes a hydrogen atom or a C1 to C3 alkyl group), a
Y-O-CO- group (in which Y denotes a C1 to C4 alkyl group) or a Z-NH-CO- group
(in which Z denotes a hydrogen atom or a C1 to C4 alkyl group), in which R
denotes a bivalent radical of the diisocyanate which is derived from isophorone
diisocyanate.
12. A composition according to claim 6, in which R denotes a bivalent
radical of the diisocyanate which is derived from isophorone diisocyanate.
13. A composition according to claim 1, in which the water-soluble
addition product of a polyetherdiol and a diisocyanate carries ionic groups.
14. A composition according to claim 13, in which the water-soluble
addition product is prepared from a polyetherdiol, which contains sulphonate
groups, and a diisocyanate.
15. A composition according to claim 14, in which hexamethylene diiso-
cyanate is used as the diisocyanate for the preparation of the water-soluble
addition product carrying ionic groups.
16. A composition according to claim 14, in which isophorone diisocyanate
is used as the diisocyanate for the preparation of the water-soluble addition
product carrying ionic groups.
17. A composition according to claim 1 wherein the active ingredient is
a water-soluble polyurethane of formula
<IMG>
18. A composition according to claim 1 wherein the active ingredient is a
polyurethane of formula
22

<IMG>
19. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
20. A composition according to claim 1 wherein the active ingredient
is a polyurethane of the formula
<IMG>
21. A composition according to claim 1 wherein the active ingredient is
a polyurethane of the formula
<IMG>
22. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
23. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
23

24. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
25. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
26. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
27. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
28. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
24

29. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>
30. A composition according to claim 1 wherein the active ingredient is
a polyurethane of formula
<IMG>

Description

~17~;~4~2
-1- Type II (Pha)
The present invention relates to the use as agents having
a tumour-inhibiting action of water-soluble addition products
of a polyether-diol and a diisocyanate~ which are in thsm-
selves known.
It has already been disclosed that complex CuII and
CoII salts of ethylene/maleic acid copolymers are active
against Walker's sarcoma (see J. Med. Chem. 12 (1969),
118û).
Polyoxyethylene sorbitane monooleate ("Tween" 80 -
Trade Mark) has already been used for immunisation against
hyperdiploid Ehrlich tumour (see Experientia 29 (1973),
710).
Furthermore, polycations of various types, for example
polyamidoamines, pbly-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, (1973), 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 groups, has also been described (see Dissertation
Abstr. Intern. B 33 (1973), 5745).
Polyanions, for example poly-(ammonium acrylate),
acrylic ac~d/acrylamide copolymers and also ethylene/
maleic anhydride copolymers are said to have~ in connection
with their tumour-inhibiting action, a heparin-like effect
and also a virus inhibition, and moreover to increase
30 the immunoreactions [see J. Med. Chem.~17 (1974), 1335].
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
Le A 20 3û8

nwnber of cases, is restricted on]y to prophylatic or adjuvant effects. Dis-
advantageously, it is moreover apparent that the investigations cited were in
many cases carried out on allogenic mouse tumours having a tendency towards spon-
taneous regression, and not systematically and under experimental arrangements
relevant to clinical conditions. Generally, there is a lack of data on the toxi-
city of the preparations, although the administration of high dosages of sub-
stances having a high molecular weight of more than 30,000 suggests inadequate
elimination, or storage in the tissues.
A block copolymer of polypropylene oxide and polyethylene oxide
~"Pluronic" F 68 - Trade Mark) has proved to be effective against the onset of
metastases of Walker's 256 ascites tumour, probably by influencing the ability
of the blood to coagulate [see Cancer 29 ~1972), 171]. As is known, these pre-
parations are highly active emulsifiers and for this reason are not very well
tolerated, in particular on parenteral administration.
W. Regelson et al. [see Nature 186 (1960) 778-780] have investigated
the tumour-inhibiting action of synthetic polyelectrolytes, such as polyacrylic
acid, polymethacrylic acid and hydrolysed or aminolysed ethylene/maleic anhy-
dride copolymers. By comparing the action of the dicarboxylic acid form, the
amidocarboxylic acid form and the diamide 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 polyacrylamides in high doses ~800 mg/kg, MW 60-70,000 and 400 mg/kg, MW
120,000) showed a negative tumour-inhibiting action or a non-significant posi-
tive twmour-inhibiting action.
Agents having a tumour-inhibiting action have likewise been described,
and are characterised in that they contain at least one water-soluble homo-
polymer or copolymer
.
.~
.
-
.

~ :~.1'7~()Z
which contains 1,3-dihydroxy-2-me-thylene-propane and/or derivatives thereof
[see DOS (German Published Specification) 2,705,189]. r~ater-soluble homopoly-
mers or copolymers which contain 3,4-dihydroxybu~-1-ene orhydroxyalkyl(meth)-
acrylate or derivatives thereof, or also derivatives of allyl alcohol, in
polymerized or copolymerized form are similar preparations with a similar action
[see DOS (German Published Specification) 2,740,082].
It has been found, surprisingly, that the water-soluble addition
products, which are in themselves known, of a polyether-diol and a diisocyanate
possess strong tumour-inhibi-ting properties.
Surprisingly, in the molecular weight range from 1,000 to 30,000,
these substances show significant curative actions against solid tumours of
syngenic systems, in a broad dosage range of 0.5 to 500 mg/kg, preferably 5 to
250 mg/kg, under experimental arrangements and methods of administra-tion
relevant to clinical conditions. The therapeutic range of the substances thus
proves to be unusually wide (LD50 on intravenous administration: >2,500 mg/kg,
therapeutic dose: 0.5 to 500 mg/kg). The agents according to the invention
thus represent an important enrichment of therapy.
According to the present invention we therefore provide a pharmaceuti-
cal composition containing as an active ingredient a water-soluble addition
product of a polyetherdiol and a diisocyanate having a molecular weight in the
range 1,000 to 30,000, in the form of a sterile and/or physiologically isotonic
aqueous solution or in the form of a tablet.
The preferred ingredients for use in the compositions according to the
invention are water-soluble oligo-urethanes or polyurethanes of the general
formula:
B ~ Q-O-CO-NH-R-N~I-CO ~ Q-O-B
in which Q denotes a polyether radical which optionally contains ionic groups,
preferably a radical of the
.
;
.
.,

79L~Z
-
--4--
general formula
A
~ 0-CH-CH2~n
wherein
A denotes hydrogen or methyl in random distribution
and
n is a number from 5 to 500 (preferably from 8
to 3~0),
the groups B are identical or difFerent and denote
a hydrogen atom` or an aliphatic, alicyclic or
aromatic radical with up to 8 carbon atoms
(preferablyahydrogen atom or Cl to C4 alkyl group);
a X-C0- group~
in which
X denotes a hydrogen atom or an aliphatic, alicyclic
or aromatic radical with up to 7 carbon atoms
(preferably a hydrogen atom or a Cl to C3 alkyl
group~;
a Y-0-C0- group,
in which
Y denotes an aliphatic, cycloaliphatic or aromatic
radical with up to 7 carbon atoms (preferably a
~Cl to C4 alkyl group); or
a Z-NH-C0- group~,
in which
Z denotes a hydrogen atom or an aliphatic, cyclo-
aliphatic or aromatic radical with up to 7 carbon
atoms (preferably a hydrogen atom or a Cl to C4
alkyl group), -
R denotes a bivalent radical oF a diisocyanate~ and
m denotes a number from 1 to 30~(preferably from
1 to 15~.
Water-soluble addition products of a polyetherdiol
and a diisocyanate which corresponds to the yeneral Formula
Le A 20 308
- ' ` ' ' ' `
`

~L~77~q;3~Z
--5--
H ~ ~OCH2CH2 ~ 0-CO-NH-R-NH-CO ~;~(OCtl2CH2 ~ 0tl
in ~hich
R has the abovementioned ~neaning,
m denotes a number from 1 to 30 and
n denotes a number from 5 to 500,
are particularly suitable as active ingredients for the compositions according
to the invention.
Diisocyanates which are particularly suitable for the preparation of
the addition products used according to the invention are hexamethylene diiso-
1~ cyc~late and isophorone diisocyanate.
In a particular embodiment of the invention, the polyaddition com-
pounds used as active ingredients contain ionic groups (such as carboxyl groups
or, preferably, sulphonate groups). It is expedient for these ionic groups to
be introduced into the polyaddition compounds by using or co-using diols which
carry the desired groups. Thus, for example, the diol of the formula
H-(O-CH2CH2 ~ O-CH2-CH-CH2-CH2-O~CH2-CH2-O ~ H
S03Na
can be employed for the preparation of an active compound carrying ionic groups.
Examples of water-soluble polyaddition compounds which are to be used
according to the invention are:
tl-~--(OCH2Ctl2 ~ o_coNH-~CH2)6-NHCO ~ ~ocH2cH2 ~ OH ~I)
H~ OCtl2Ctl2 ~ O-CONH-~CH2)6-NHCO ~ ~OCH2CH2 ~ OH ~II)
H-~-(OCH2CH2 ~ O-CONH-(CH2)6-NHCO ~ (CH2CH2 ~ OH ~III)
H-~-~ocH2cH2~---O-CONH-~cH2)6-NHCO ~ ~ocH2cH2~ oH ~IV)
H-t--~OCH2CH2~--- O-CONH-~CH2)6-NHCO~ OCH2CH2~ OH ~V)
~r

-6- ~ 2
H ~ ~OCH2CH2~ O- CONII- (CH2) 6-NHCO ~ (CH2CH2~ OH (VI)
3 3
H~(OCH2C~12~ O-CO-HN- ~ 2 4 35 (VII)
CH3 3
H--~OCH2CH2~ O-COHN-H[~ CH2 2 68 (VIII)
3 CH3
H~(ocH2cH~t O-COHN- ~ 2 2 35 (IX)
3,~<~ 3
35 CH3-NHco~(ocH2cH2~oH (X)
3 3
H~ (CH2CH2~ O-COHN- ~< CH3-NHCO~(OCH2CH~OH (XI)
3 3
H~(OcH2cH2~ O-CO-HN- ~ CH3-NHCO~(OC~12CH2~8 OH (XII)
X
` . ~ ~ ~ , ,` .
.

7_ ~77~
C113 C~13
H ~ ( CH2 CH2~ 0Ctl2 - fl- CH2- CH2- O- (CH2 CH2 - 03--CNH- ~!~ cC~123
S03Na
_ ~XI I I)
_
lNH-CO~(OC}I2CH2~O-CH2-fI-CH2-CH2 ( 2 2 7
S03Na
CH3 3
~( f 2~3 OCH2-ICH-CH2-CtI2-O-~CH2CH-O~CONH-~CHH23
CH3 SO3Na CH3
~XIV)
LNH-CO~ ~CHCH2~ Ctl2-CH-CH2-CH2-O ~CH2CIH OtH
CH3 SO3Na CH3
The water-soluble polyaddition products which represent the active com-
pounds according to the invention are prepared by processes wh:ich are in them-
selves known. They are obtained by reacting polyether-glycols which have vari-
ous chain lengths and can optionally contain ionic groups, such as sulphonate
groups, carboxylate groups or ammonium groups, with diisocyanates, in particular
with hexamethylene diisocyanate or isophorone diisocyanate.
These reactions are carried out in an inert solvent, such as, prefer-
ably, chloroform or methylene chloride. The ratio of diol to diisocyanate is
chosen such that molecule chains greater or shorter in length result, in a con-
trolled manner. Less than the equivalent amount of diisocyanate is always
employed, so that polymers with OH end groups are formed. The reaction tempera-
ture is room temperature to the boiling point of the solvent. The reaction time
is 2 to 8 hours.
.

-8- ~ 40~
The hydroxyl end groups of the oligo-urethanes or polyurethanes can be
converted into ether groups, carboxylic acid ester groups, carbonic acid ester
groups or urethane groups by known methods.
Examples which may be mentioned of alkylating agents for etherifying
the hydroxyl groups are dialkyl sulphates, alkyl halides and esters of p-toluene-
sulphonic acid
.

7~QZ
,
g
[see Organikum, Oryanisch-chemisches Grundpraktikum
(Basic Manual of Organic Chemistry), 6th edition, Berlin
1967, pages 185 et seq.]. Carboxylic acid ester
groups can be introduced, for example, by the action
of acid anhydrides in the presence of an acid catalyst
or by reactionlwith acid chlorides in the presence of
a tertiary amine. Carbonic acid ester,,groups can be
produced by reaction with chloroformic acid estersin
the presence of inert bases.
If mixtures of diisocyanates and monoisocyanates
are employed in the preparation of the polyurethane,
products with urethane end groups are obtained.
When the reaction has ended, the solvent is
removed, preferably by being distilled off,in vacuo.
Liquid or viscous to solid substances are obtained,
which can be characterised by their melting point or their
refractive index and which are soluble in water or in
physiological sodium chloride solution, in some cases
with a slight cloudiness, to give solutions of at least
2û 0.5 ~ strength by weight.
In addition to an exceptionally low toxicity,
the agents according to the invention have a strong
tumour-inhibiting action against tumours in animals
and humans and are therefore intended for use in combating
illnesses caused by tumours.
The agents according to the invention are prepared
by dissolving the active compounds in physiological
sodium chloride solution.
As stated above, the invention also relates to the
use in human and veterinary medicine as antitumorial ag,ents
of 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
Le A 20 308

~'7~7~
-10-
comprises administering to the animals a compound of the invention in admixture
with a diluent. For parenteral administration such solutions should be sterile
and; if appropriate blood isotonic.
It is envisaged that these active compounds will be administered
parenterally (for example intramuscularly, intraperitoneally, subcutaneously and
intravenously)-systemically or locally-preferably intraperitoneally, intraven-
ously or intramuscularly. Preferred pharmaceutical compositions and medicaments
are therefore those adapted for administration such as intraperitoneal, intraven-
ous or intramuscular administration. Administration in the method of the inven-
tion is preferably intraperitoneal, intravenous or intramuscular administration.~lowever, peroral administration is possible, too.
In general it has proved advantageous to administer amounts of from
0.5 mg to 500 mg/kg, preferably 5 mg to 250 mg/kg, of body weight per day to
achieve effective results. Nevertheless, it can at times be neccssary to devi-
ate from those dosage rates, and in particular to do so as a function of the
nature and body weight of the human or animal subject to be treated, the indivi-
dual reaction of this subject to the treatment, the type of fGrmulation in which
the active ingredient is administered and the mode in which the administration
is carried out, and ~he point in the progress of the disease or interval at
which it is to be administered. Thus it may in some cases suffice to use less
than the above-mentioned minimum dosage rate, whilst in other cases the upper
limit mentioned must be exceeded to achieve the desired results. Where larger
amounts are administered it can be advisable to divide these into several indivi-
dual administrations over the course of the day.
The unusual breadth of the abovementioned therapeutic dosage range is
based on the unusual non-toxicity of the active compounds.
The substances listed in Table 1 were tested for this induction of

~17~4~2
- 11-
tumour-inhibiting action on mouse sarcoma MCS 4 and on carcinoma EO 771 in
numerous experiments, under various test conditions.
The method of the investigations on these two experimental tumours are
given in the following experimental descriptions (a) and ~b).
Description of experiments a?
Tumour tests against carcinoma E0 771 in C 57 BL/6 mice
_ _ _ . _ _ _ _
Animal strain: C 57 BL/6 mice, inbred (SPF)
Methods:
Maintaining the tumour 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
0.9 % phosphate-buffered NaCl solution (PBS) into C 57 BL/6 mice.
Preparation of screening tests: Same process as in maintaining the strain of
the tumour, but subcutaneous inoculation of a suspension of 5 x 104 tumour cells
in 0.5 ml of 0.9 % PBS.
Treatment: Single intramuscular injection of the required solution of the sub-
stances 6 days prior to or 2 days after the tumour transplantation.
Duration of experiments: 18-22 days after the tumour transpla;ltation. There-
after, sacrificing of the animals, preparation and weighing of the subcutaneous
tumours.
Evaluation parameters: Inhibition of the tumour growth by determination of the
average tumour weight of control animals and groups of treated ~nimals, as well
as calculation of the tumour weight (TW) index according to the formula:
Tl~ index = 0 tumour weight of the groups of treated animals
~ tumour weight of the control group
Assessment of the test results:
n~ index 0.8 - 0.6 = marginal activity
0.6 - 0.4 = moderate activity
0.4 - 0.0 = good activity
X

77~
-12-
Description of experiments b)
Tumour tests against sarcoma MCS 4 in C 57 BL!6 mice
Malntaining the tumour strain: 10-14 days after the last transplantation, sub-
cutaneous inoculation of a suspension of cells of sarcoma MCS 4 in 0.5 ml of
0.9 % phosphate-buffered NaCl solution (PBS) into C 57 BL/6 mice.
Preparation of screening tests: Same process as in maintaining the strain of
the tumour, but subcutaneous inoculation of a suspension of 2 x 105 tumour cells
in 0.5 ml of 0.9 % PBS.
Treatment: Single intravenous injection of the required solution of substances
2 days prior to or 2 days after the tumour transplantation.
Duration of experiments: 18-22 days after the tumour transplantation. There-
after, sacrificing of the animals~ preparation and weighing of the tumours.
Evaluation and assessment of the results are carried out analogously to the des-
-
cription of experiments a).
Overall assessment of the results in Tables 1 and 2
The tumour weight indices of the preparations listed in Tables 1 and 2
show that the substances at various doses, by various methods of administration,
and also on various days of treatment are capable of inducing distinct tumour-
-inhibiting activity both against sarcoma MCS 4 and against carcinoma EO 771.

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Le A 20 308
.

-14- ~77~Z
The following Examples illustrate the production of active ingredients
used in the compositions of the present invention.
Example 1
Water-soluble polyurethane of the formula (I)
H~¦OCH2CH2~0-CO-NH-~CH2)6-NH-CO~(OC~l2cH2~0H
A solution of 50.5 parts by weight of a polyglycol with an average
molecular weight of 1,000 in 50 parts by volume of chloroform was initially
introduced into a closed three-necked stirred apparatus which was equipped with
a thermometer, dropping f~mnel and reflux condenser. A solution of 6.7 parts by
weight of hexamethylene diisocyanate in 50 parts by volume of chloroform was
added dropwise, whilst stirring continuously. After subsequently stirring the
mixture at 50C for 2 hours, the solvent was evaporated off in a rotary evapo-
rator. A crystalline water-soluble substance was obtained. Melting point: 42 C.
Example 2
Polyurethane of the formula ~II)
H-~-~OCH2CH2~--0-CO-NH-(CH2)6-NH-CO~ OCH2CH2~--OH
A solution of 6.7 parts by weight of hexamethylene diisocyanate in 50
parts by volume of chloroform was added to 15 parts by weight of a polyglycol
with an average molecular weight of 300, dissolved in 50 parts by volume of
chloroform, as described in Example 1. The mixture was allowed to react com-
pletely at 50C by stirring for 2 hours, and~ finally, the solvent was stripped
off in a rotary evaporator. A viscous, water-soluble liquid with a refractive
index nD of 1.4876 resulted.
Example 3
Polyurethane of the formula
H~ OCH2CH2 t 0-CO-NH-~CH2~6-NH-CO-}~-~OcH2cH2~---- OH

g~77~(1Z
-15-
20 parts by weight of a polyglycol with an average molecular weight of
about 400 were reac~ed with 6.7 parts by weight of hexamethylene diisocyanate in
chloroform, analogously to Example 1. A viscous liquid which was readily water-
-soluble and had a refractive index nD of 1.4850 was obtained.
Example 4
Polyurethane of the formula ~VI)
H-~-(OCH2CH2~----- o-CO-NH-(CH2)6-NH-CO-~--(OC~12CH2~---OH
150 parts by weight of a polyglycol with an average molecular weight
of 3,000 were reacted with 6.7 parts by weight of hexamethylene diisocyanate in
methylene chloride, as described in Example 1. After evaporating off the solvent,
a crystalline substance which was soluble in water, giving a slightly turbid
solution, was obtained. Melting point: m.p. = 53C.
Example 5
Polyurethane of the formula
H-~-~OCH2CH21--- O-co-NH-(cH2)6-NH-co-~ ocH2cH2l--- OH
A water-soluble crystalline substance with a melting point m.p. of
45 C was obtained by reacting 77.5 parts by weight of a polyglycol with an aver-
age molecular weight of 1,550 with 6.7 parts by weight of hexamethylene diiso-
cyanate.
Example 6
Polyurethane of the formula
3 CH3
H-~-(OCH2CH2~----O-CO-NH- ~ CH3-N~I-CO-~--(OCH2CH2~0H
A solution of 8.9 parts by weight of isophorone diisocyanate in 50
parts by volume of chloroform was added to a solution of 15 parts by weight of a

~.77~02
-16-
polyglycol with an average molecular weight of 300 in 50 parts by volume of
chloroform, analogously to Example 1. After subsequently stirring the mixture
a~ 50C for 2 hours, the chloroform was evaporated off in a rotary evaporator.
A slightly viscous liquid which was very readily soluble in water was obtained.
Refractive index nD = 1.4952.
Example 7
Polyurethane of the formula (VII)
>~
~12Cl~2~ -C-NH- U C 2 4 35
77.5 parts by weight of a polyglycol with an average molecu~ar weight
of 1,550 were reacted with 8.9 parts by weight of isophorone diisocyanate analo-
gously to Example 1. The resulting polyurethane was a crystalline substance,
which was readily soluble in water to give a 10 % strength solution. Melting
point: m.p. = 56C.
Example 8
Polyurethane of the formula
3 3
(OCH2CH2~ o-co-NH- ~ c 2 4 2 68
A polyurethane which was soluble in water, giving a slightly turbid
solution, and has a melting point m.p. of 47 C was obtained from 150 parts by
weight of a polyglycol with an average molecular weight of 3,000 and 8.9 parts
by weight of isophorone diisocyanate.
Example 9
Polyurethane of the formula

-17- ~77402
Cil3 C113
(0c~l2cll2~-O-Co-NH- ~ CH2 2 2 2 68
102 parts by weight of a polyglycol with an average molecular weight
of 3,000 were reacted with 5 parts by weight of isophorone diisocyanate as des-
cribed in Example l. A crystalline substance which was very readily soluble in
water and had a melting point m.p. of 54C was obtained.
Example 10
Polyurethane of the formula (XI)
~l ~ l3
H-~-~OCH2CH2~ 0-C0-NH- ~ 2 7 7
A slightly viscous li~uid which was readily soluble in water and had a
refractive index nD of 1.4968 was obtained by reacting 24 parts by weight of a
polyglycol with an average molecular weight of 300 with 15.5 parts by weight of
isophorone diisocyanate in chloroform and evaporating off the solvent in a
rotary evaporator.
Example 11
Polyurethane of the formula
~1 ~ (oc~l2cH2~ O-cO-NH-~c~l2)6-NH-co-t~-~ocH2cH2~ OH
After reacting 120 parts by weight of a polyglycol with an average
molecular weight of 3,000 with 4.5 parts by weight of hexamethylene diisocyanate
in methylene chloride, and after evaporating off the solvent in vacuo, a crystal-
line substance which was readily soluble in water and had a melting point m.p.of 55C was obtained.
Example 12
Polyurethane of the formula ~IX)
,
.

-18- 1~4~
3 3
(OCH2cil2~---o-co-NH- ~ 2 2 35
93 parts by weight of a polyglycol with an average molecular weight of
1,550 and 8.9 parts by weight of isophorone diisocyanate were reacted with one
another in chloroform. After evaporating off the solvent in vacuo, a crystal-
line substance which was readily soluble in water was obtained. Malting point:
m.p. = 49C.
Example 13
Polyurethane of the formula ~X)
H-(OCH2CH2~--- O-CO-NH- ~ CHH3-NH-CO-(OCH2CH2- } OH
124 parts by weight of a polyglycol with an average molecular weight
of 1,550 and 8.9 parts by weight of isophorone diisocyanate were reacted with
one another in chloroform. After evaporating off the solvent, a crystalline sub-
stance which could readily be dissolved in water was obtained. Melting point:
m.p. - 56C.
Example 14
Polyurethane of the formula (XIV)
3 3
H-~-(OCI~I-C~12~--0CH2-CH-CH2-CH2-0-(CH2CH-O~--CONH- ~ CH23
CH3 S03Na CH3
. _
lNH-CO ~ (OCHCH2 ~ 0-CH2-CIH-CH2-CH2 O-(CH2C~I-O ~ H
CH3 S03Na CH3

-19- ~774VZ
254 parts by weight of the sulphonate-diol of the formula
H-(OCHCH23-- 0CH2-CH-CH2-CH2-0-
~
CH3 S03Na CH3
were dissolved in 500 parts by volume of toluene, and the solution was warmed tothe reflux temperature. 83 parts by weight of isophorone diisocyanate were then
added slowly. After subsequently stirring the mixture for 2 hours, the toluene
was distilled off in vacuo. A crystalline substance which was readily soluble
in water was obtained.
,d~
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-