The invention concerns novel cross-linked poly(N,N-dialkylallyl)ammonium polymer materials containing quaternary propylammonium structural units which are effective in lowering elevated plasma levels of low density lipoproteins and lipoid components thereof, such as cholesterol, and which are of value in the treatment of conditions in which such elevated plasma levels are associated, for example, various vascular diseases. The invention also provides methods for the manufacture of the polymer materials and various intermediates for use in such manufacture.

TECHNICAL FIELD 
This invention concerns novel nitrogen derivatives and, more particularly, 
novel polymeric materials which contain quaternary ammonium groups, which 
materials are valuable in the reduction of elevated levels in blood plasma 
of low density lipoproteins (LDL) and lipoid components thereof such as 
cholesterol. Such elevated levels of LDL and cholesterol are frequently 
associated with vascular disease and related conditions, such as 
atherosclerosis and coronary heart disease. The invention also provides 
processes for the manufacture of, and pharmaceutical compositions 
containing the novel nitrogen derivatives, as well as therapeutic and/or 
prophylactic methods of treatment by administering the nitrogen 
derivatives. 
BACKGROUND TO THE INVENTION 
A number of agents are well known to reduce elevated levels of LDL and 
cholesterol, for example hypocholesterolaemic agents such as clofibrate, 
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors such 
as simvastatin and fluvastatin as well as agents which act by complexing 
with bile acids in the intestinal system. Illustrative of such latter 
agents is that known as cholestyramine described, inter alia, in UK patent 
Ser. No. 929,391 and which is a cross-linked polystyrene resin in which a 
proportion of the styrene units bear an ionic trimethylammonium group. It 
is believed that many of such agents act by sequestering bile acids within 
the intestinal tract, thus lowering levels of bile acid circulating in the 
enterohepatic system and promoting replacement of bile acids by synthesis 
in the liver from cholesterol, which synthesis results, inter alia, in a 
lowering of circulating blood cholesterol levels. The use of bile acid 
sequestering agents such as cholestyramine and colestipol in treating 
conditions such as familial hypercholesterolaemia is known, as is their 
use in preventing or limiting the progression of diseases such as coronary 
heart disease associated with high levels of blood lipids such as 
cholesterol, and in alleviating adverse conditions affecting the 
intestinal tract such as diarrhea. However, there is a continuing need for 
new alternative agents, in particular because many of the existing agents 
are not particularly potent and produce adverse side-effects. Thus, it is 
frequently necessary to administer comparatively large amounts (up to 25 g 
daily) of presently available polymeric agents, such as cholestyramine and 
colestipol, to produce a beneficial effect. Patient compliance with dosing 
regimes involving such large amounts of relatively unpalatable polymeric 
agents is difficult to achieve. 
Insoluble poly(allylamine) polymeric materials have been known for some 
time, for example as described in European patent application, publication 
no. 143,328 pending. However, they have not previously been known to be of 
value as pharmaceutical agents. We have now discovered, and this is a 
basis for our invention, that a series of novel, polymeric allylamine 
derivatives containing quaternary ammonium groups possess useful activity 
in reducing plasma sterol levels (for example, cholesterol levels) at 
relatively low doses and with a reduced propensity towards the production 
of significant side-effects. 
DISCLOSURE OF THE INVENTION 
According to the invention there is provided an insoluble, swellable 
polymeric allylammonium derivative (D1) comprising in essentially random 
order: 
(i) at least 10 mole percent of quaternary propylammonium structural units 
of the empirical formula I (set out hereinafter) wherein one of R.sup.1, 
R.sup.2 and R.sup.3 is (1-16C)alkyl (4-12C)cycloalkyl or 
phenyl-(1-4C)alkyl, the latter phenyl moiety optionally bearing one or two 
substituents, independently selected from halogeno, (1-4C)alkyl and 
(1-4C)alkoxy; another of R.sup.1, R.sup.2 and R.sup.3 is (1-4C)alkyl; and 
the other of R.sup.1, R.sup.2 and R.sup.3 is (1-4C)alkyl optionally 
bearing a carbamoyl substituent, or is (2-4C)alkyl bearing a hydroxy 
substituent on other than an .alpha.-carbon atom; and Y is a 
physiologically acceptable anion; 
(ii) about 0.5 to 10 mole percent of cross-linking structural units 
substantially of the empirical formula IIa and/or IIb (set out 
hereinafter) wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are 
independently hydrogen or one of the values of R.sup.1, R.sup.2 and 
R.sup.3 defined above; one of R.sup.9 and R.sup.10 is hydrogen or 
(1-4C)alkyl and the other of R.sup.9 and R.sup.10 has one of the values of 
R.sup.1, R.sup.2 and R.sup.3 defined above; Y has the meaning defined 
above; and X is a cross-linking group; and 
(iii) the remainder substantially of structural propylamino units of the 
empirical formula III (set out hereinafter) wherein R.sup.11 and R.sup.12 
are independently hydrogen or one of the values of R.sup.1, R.sup.2 and 
R.sup.3 defined above, and Y has the meaning defined above; and said 
derivative D1 having the property of swelling in volume in at least one of 
water, 0.15M aqueous sodium chloride solution, and ethanol by between 
about 2 and 200 times. 
It will be understood that the polymeric allylammonium derivatives D1 can 
have an indeterminately high molecular weight since cross-linking produces 
a polymer matrix including the repeating structural units of formula IIa 
and/or IIb. It will also be understood that the cross-linking groups 
within any particular polymeric allylammonium derivative D1 of the 
invention may be the same or different structural units of the empirical 
formula IIa or IIb, that is they may differ in the degree of substitution 
on the nitrogen atoms. Further, it will be understood that the polymeric 
allylammonium derivatives D1 may include quaternary propylammonium 
structural units of empirical formula I which have different combinations 
of values for R.sup.1, R.sup.2 and R.sup.3 In addition, although the 
structural units IIa, IIb and III depict the nitrogen atoms in a 
quaternary cationic configuration, it will be apparent to those skilled in 
the art that as a result of steric and inductive factors the derivatives 
D1 may also contain a small proportion of analogous structural units in 
which a nitrogen atom may be present as a free, uncharged primary, 
secondary or tertiary amino group, that is in which no anion Y is present. 
Illustrative values for R.sup.1, R.sup.2 and R.sup.3 include for example: 
for (1-16C)alkyl, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, 
pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl, octyl, 
nonyl, decyl, undecyl, dodecyl and tetradecyl [of which values, methyl, 
butyl, 3-methylbutyl, hexyl, octyl and dodecyl of are particular 
interest]; 
for (1-4C)alkyl, methyl, ethyl, propyl and butyl; 
for (1-4C)alkyl optionally bearing carbamoyl, methyl, ethyl, propyl and 
butyl optionally bearing a carbamoyl substituent; 
for (2-4C)alkyl bearing a hydroxy substituent on other than an 
.alpha.-carbon atom, 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl; 
for cycloalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-octyl and 
cyclododecyl; and 
for phenylalkyl, benzyl, 1-phenylethyl, 2-phenylethyl and 3-phenylpropyl. 
Particular values for R.sup.8 or R.sup.9 when it is (1-4C)alkyl are, for 
example, methyl ethyl or propyl. 
Particular substituents which may be present on a phenyl group when one of 
R.sup.1, R.sup.2 and R.sup.3 is phenylalkyl include for example: for 
halogeno, fluoro, chloro and bromo; for alkyl, methyl, ethyl and 
isopropyl; and for alkoxy, methoxy and ethoxy. 
Preferred values for R.sup.1, R.sup.2 and R.sup.3 include, for example when 
one is methyl, butyl, hexyl, 3-methylbutyl, octyl, dodecyl or benzyl, and 
the others are methyl. 
A specific group of values for the cross-linking group X includes, for 
example: polymethylene of up to 14 carbon atoms (such as trimethylene, 
tetramethylene, hexamethylene, octamethylene, decamethylene and 
dodecamethylene), optionally containing one or more hydroxy substituents 
(such as 2-hydroxytrimethylene and 2,7-dihydroxyoctamethylene); and 
poly(ethyleneoxy)ethylene of the formula --[CH.sub.2 CH.sub.2 O].sub.n 
CH.sub.2 CH.sub.2 -- in which n is an integer from 1 to 6 (such as 
tri(ethyleneoxy)ethylene). Particularly preferred values for X include, 
for example, trimethylene, 2-hydroxytrimethylene and dodecamethylene. 
Particular values for the physiologically acceptable anion Y include, for 
example, ions from strong acids such as halide (especially chloride), 
sulphate and phosphate, as well as ions from organic acids such as 
acetate, propionate, lactate, citrate, tartrate and gluconate. 
One particular group of polymeric allylammonium derivatives D2 of the 
invention comprises derivatives D1 as defined above wherein the total 
amount of quaternary substituted amino containing units of the empirical 
structural formula I, IIa and/or IIb constitutes at least 15 mole percent 
of the polymeric allylammonium derivative. 
A further particular group of polymeric allylammonium derivatives D3 of the 
invention comprises derivatives D1 or D2 as defined above wherein in 
addition in at least 75% of the structural units of formula I the group 
--NR.sup.1 (R.sup.2)(R.sup.3) is selected from --N(CH.sub.3).sub.3, 
--N(CH.sub.3).sub.2 (butyl), --N(CH.sub.3).sub.2 (hexyl), 
--N(CH.sub.3).sub.2 (3-methylbutyl), --N(CH.sub.3).sub.2 (benzyl), 
--N(CH.sub.3).sub.2 (octyl) and --N(CH.sub.3).sub.2 (dodecyl). 
A preferred value for the linking group X in empirical formula IIa is, for 
example, trimethylene or dodecamethylene. 
Preferred polymeric amine derivatives will generally swell in volume in at 
least one of water, 0.15M aqueous sodium chloride solution, and ethanol, 
by, for example, about 3 to 75 times. 
One preferred group of polymeric allylammonium derivatives D4 of the 
invention includes insoluble, swellable polymeric allylammonium 
derivatives comprising in essentially random order: 
(i) at least 60 mole percent of quaternary propylammonium structural units 
of the empirical formula I in which the group --NR.sup.1 
(R.sup.2)(R.sup.3) may be --N(CH.sub.3).sub.3, --N(CH.sub.3).sub.2 
(butyl), --N(CH.sub.3).sub.2 (hexyl), --N(CH.sub.3).sub.2 (octyl) or 
--N(CH.sub.3).sub.2 (dodecyl); 
(ii) about 3 to 8 mole percent of cross-linking structural units 
substantially of the empirical formula IIa in which the group of the 
formula --N(R.sup.5)(R.sup.6)--X--N(R.sup.7)(R.sup.8)-- may be 
--N(CH.sub.3).sub.2.CH.sub.2.CH.sub.2.CH.sub.2.N(CH.sub.3)2--, 
--NH(CH.sub.3).CH.sub.2.CH.sub.2.CH.sub.2.N(CH.sub.3).sub.2 -- or 
--NH(CH.sub.3).CH.sub.2.CH.sub.2.CH.sub.2.NH(CH.sub.3)--; and 
(iii) the remainder substantially of propylamino structural units of the 
empirical formula III in which the group --NH(R.sup.11)(R.sup.12) is 
--NH(CH.sub.3).sub.2 ; 
Y is halide (especially chloride) or a physiologically acceptable organic 
acid anion (especially citrate); 
and which derivatives have the property of swelling in volume in at least 
one of water, 0.15M aqueous sodium chloride and ethanol by about 3 to 30 
times. 
The corresponding free base forms of the polymeric allylammonium 
derivatives D1, D2, D3 and D4 may be readily obtained from the 
corresponding salt forms by removal of the acid corresponding to the anion 
Y, for example by treatment with a strong base, for example an alkali 
metal hydroxide such as sodium hydroxide. Although the polymeric 
allylammonium derivatives of the invention are generally more stable and 
easily isolable as the salt forms defined hereinabove, the corresponding 
free base forms of the polymeric allylammonium derivatives D1, D2, D3 and 
D4 are also useful, for example when it is required to produce a salt 
containing an alternative anion by reaction with the appropriate acid of 
the formula HY where Y has the meaning defined above, and are included as 
a feature of the invention. 
It will be recognised that, for the free base form of the polymeric 
allylammonium derivatives D1, the anion Y will be hydroxide. It will be 
understood that, in such free base forms: 
(a) cross-linking groups of empirical formula IIa may themselves contain 
one or two quaternary ammonium hydroxide groups, or secondary or tertiary 
amino groups; 
(b) cross-linking groups of empirical formula IIb may themselves contain a 
quaternary ammonium hydroxide group, or a tertiary amino group; and 
(c) propylamino groups of empirical formula III may themselves contain a 
primary, secondary or tertiary amino group; 
in each case depending on the nature of the substituents R.sup.5 to 
R.sup.12 therein. 
Typical polymeric allylammonium derivatives of the invention are described 
in the accompanying Examples. Of these, derivatives of particular interest 
include, for example, those produced by the procedures described in 
Example 2, 36, 38, 48, 52 and 58, which derivatives are provided either as 
the indicated chloride salt form (or as an alternative salt form) as a 
further feature of the invention. 
The polymeric allylammonium derivatives of the invention may be 
manufactured by standard procedures well known in the art for the 
production of analogous polymeric amines. The invention further provides a 
process for the manufacture of a polymeric allylammonium derivative as 
defined above using such an analogous procedure. 
One preferred process of the invention is characterised by alkylating a 
cross-linked poly(allylamine) derivative (E) which comprises in 
essentially random order: 
(i) at least 10 mole percent of secondary and/or tertiary substituted 
propylamino structural units of the empirical formula (IV) [set out 
hereinafter] wherein one of R.sup.13 and R.sup.14 is (1-16C)alkyl, 
(4-12C)cycloalkyl or phenyl(1-4C)alkyl optionally substituted as defined 
above, and the other of R.sup.13 and R.sup.14 is hydrogen, (1-4C)alkyl 
optionally bearing a carbamoyl, or (2-4C)alkyl bearing a hydroxy 
substituent on other than an .alpha.-carbon atom; 
(ii) about 0.5 to 10 mole percent of cross-linking structural units 
substantially of the empirical formula Va, Vb and/or Vc [set out 
hereinafter] wherein R.sup.15 R.sup.16 and R.sup.17 are independently 
hydrogen or one of the values of R.sup.13 and R.sup.14 defined in (i) 
above, and R.sup.18, R.sup.19, R.sup.20 and R.sup.21, independently, have 
any of the values of R.sup.13 and R.sup.14 defined in (i) above except 
hydrogen, and, in formula Vc, Y is an anion; and 
(iii) the remainder substantially of structural propylamino units of the 
formula VI [set out hereinafter] wherein R.sup.22 has one of the values of 
R.sup.13 and R.sup.14 defined above apart from hydrogen; by reaction with 
a suitable alkylating agent; whereby at least 10 mole percent of 
quaternary substituted amino groups as defined above for D1, D2, D3 or D4, 
is introduced therein. 
Specific values for the generic radicals R.sup.13 -R.sup.22 and the anion Y 
include, for example, those given for the analogous generic radicals 
defined for D1, D2, D3 and D4 above. 
The invention further provides a polymeric allylammonium derivative 
produced by carrying out the above process, or by an obvious chemical 
variation thereof, for example as is illustrated in the Examples 
hereinafter. One such variation which may be conveniently employed when 
differently substituted quaternary amino groups are required in the 
polymeric allylammonium derivative D1, D2, D3 or D4 is to carry out the 
alkylation in two stages using first one and then the other required 
alkylating agent, for example first using appropriate amounts of the 
higher molecular weight alkylating agent and then of the lower molecular 
weight alkylating agent. 
It will be understood that in the present specification the term 
"alkylation" embraces the introduction of alkyl, cycloalkyl and 
phenylalkyl groups. The alkylation may be performed by any standard 
alkylation procedure well-known in the chemical art, for example, by 
reaction with the appropriate alkyl, cycloalkyl or phenylalkyl bromide or 
iodide, or with an analogous alkylating agent such as a dialkyl sulphate, 
to give the corresponding polymeric allylammonium derivative in which Y is 
bromide or iodide, (or sulphate or alkylsulphato when a dialkyl sulphate 
is used as the alkylating agent). The alkylation process is conveniently 
carried out in the presence of a suitable solvent or diluent, for example, 
ethanol, propanol or N,N-dimethylformamide and at a temperature in the 
range 20.degree. to 80.degree. C. 
It will be appreciated that when a different anion is required than is 
produced in the alkylation reaction, this anion may be obtained, for 
example, by reacting said polymeric allylammonium derivative with a 
solution of a suitable salt of the formula M.Y.sup.1 in which M is an 
alkali metal or alkaline earth metal (especially sodium or potassium) and 
Y.sup.1 is the anion. Alternatively, the polymeric allylammonium 
derivative may be converted to its free base form, for example, by 
reaction with a solution of an alkali metal hydroxide such as sodium or 
potassium hydroxide, which free base form may then be reacted with the 
appropriate acid H.Y.sup.1 in which Y.sup.1 is the desired anion. 
The starting cross-linked poly(allylamine) derivatives E are provided as a 
still further feature of the invention and may be made by a number of 
alternative procedures, for example, as are described in the accompanying 
Examples. Typical procedures include the following: 
(a) The reaction of a linear poly(allylamine) of the formula VII in which m 
is an integer and of an average molecular weight in the range about 7000 
to 85000, with an aldehyde of the formula R.sup.23 CMO wherein R.sup.23 is 
hydrogen, (1-15C)alkyl, phenyl or phenyl-(1-3C)alkyl, the phenyl in the 
latter two groups optionally bearing as a substituent, halogeno, 
(1-4C)alkyl or (1-4C)alkoxy, or with an acyclic (3-16C)ketone or cyclic 
(4-12C)ketone, under reducing conditions, and optionally followed by 
reaction with a suitable cross-linking agent. 
Particular values for R.sup.23 include, for example, hydrogen and the 
corresponding values for R.sup.13 or R.sup.14 (except methyl) with one 
less terminal carbon atom. Thus, when a derivative E is required in which 
R.sup.13 or R.sup.14 is butyl, then an aldehyde of the formula 
R.sup.23.CHO in which R.sup.21 is propyl i.e. butyraldehyde is used. 
Similarly, when a derivative is required in which R.sup.13 or R.sup.14 is 
an .alpha.-branched alkyl, the corresponding ketone is used. It will be 
understood that when the aldehyde of formula R.sup.23.CHO is formaldehyde 
then a derivative E results in which R.sup.13 and R.sup.14 are both methyl 
generally results. 
Procedure (a) is an example of a so-called reductive alkylation and 
reducing conditions generally analogous to those well known in the art for 
such reactions may be used. The reducing conditions are generally produced 
by use of a suitable reducing agent such as an alkali borohydride or 
cyanoborohydride, for example, sodium or potassium borohydride or 
cyanoborohydride. In general, the reductive alkylation in procedure (a) is 
performed at a temperature in the range, for example, 5.degree. to 
30.degree. C. and, conveniently, at or near ambient temperature. A 
suitable solvent or diluent such as a (1-4C)alkanol, tetrahydrofuran or 
t-butyl methyl ether, may conveniently be used for the process (a). 
(b) When a derivative B is required in which R.sup.13 and R.sup.14 are both 
methyl is required, the reaction of a linear poly(allylamine) of the 
formula VII in which n is an integer and of an average molecular weight in 
the range about 7000 to 85000, with formaldehyde in the presence of formic 
acid, optionally followed by reaction with a suitable cross-linking agent. 
Procedure (b) is an example of the well known Eschweiler-Clarke reductive 
methylation reaction and conditions similar to those known for analogous 
methylations may be used, for example, using an excess of formaldehyde 
(conveniently as an aqueous solution) in formic acid at a temperature in 
the range, for example 60.degree.-100.degree. C. and conveniently at or 
near the reflux temperature of the reaction mixture. 
The linear poly(allylamines) of formula VII are in general known or may be 
obtained by procedures well known in the art for analogous compounds. 
Thus, they are described in European patent application, publication no. 
95,233 and are commercially available from Nitto Boseki Company Ltd., of 
Fukushima-ken, Japan. 
It will be understood that in many cases (and especially when a linear 
(2-6C)alkyl group is being introduced) the reductive alkylation procedure 
may introduce a proportion of cross-linking structural units of formula Va 
into the polymeric allylammonium derivative, the proportion introduced 
depending on factors such as the relative stoichiometry of the reagents of 
formula VII and the ketone or aldehyde component (which latter may 
conveniently be used in the form of its hydrate or acetal). This so-called 
self cross-linking may of its own be sufficient to impart the required 
swelling capacity to the eventual polymeric allylammonium derivatives D of 
the invention to make them suitable for the above mentioned pharmaceutical 
use. However, in other cases, for example when a .beta.-branched alkyl is 
being introduced using a suitable aldehyde, or when an a-branched alkyl is 
being introduced using an acyclic or cyclic ketone, then little or no such 
self cross-linking occurs during the reductive alkylation procedure (a). 
In such cases, it is necessary to specifically cross-link the initially 
formed linear poly(N-alkylallylamine) by reacting it with a suitable 
cross-linking agent, for example of the formula L.sup.1 -X-L.sup.2 in 
which X has the meaning defined above and L.sup.1 and L.sup.2 are suitable 
leaving groups, such as chloride, bromide, iodide, methanesulphonate, 
benzenesulphonate or p-toluenesulphonate. Alternatively, for those 
derivatives where X is (3-14C)polymethylene bearing a hydroxy group on the 
second carbon atom or (4-14C)polymethylene bearing two hydroxy groups on 
the second and penultimate carbon atoms, the cross-linking agent may be 
the appropriate epoxy or diepoxy derivatives of the formula: 
##STR1## 
in which X.sup.1 is (1-12C)polymethylene, X.sup.2 is (1-10C)polymethylene 
and L.sup.3 is a suitable leaving group such as one of those defined above 
for L.sup.1 or L.sup.2 Such specific cross-linking reactions may 
optionally be performed in the presence of a base, for example, an alkali 
metal hydroxide or carbonate, such as sodium hydroxide or potassium 
carbonate, and conveniently carried out in the presence of a suitable 
solvent or diluent such as N,N-dimethylformamide and at a temperature in 
the range, for example, 10.degree. to 50.degree. C. The above 
cross-linking reaction conditions may conveniently be modified by 
including a non-miscible solvent or diluent, for example, toluene, xylene 
or chlorobenzene, to the reaction mixture so that an emulsion is produced. 
General conditions for carrying out such modified cross-linking are 
described, for example in U.S. Pat. No. 4,605,701. 
Procedure (a) or (b) may conveniently be modified by first cross-linking a 
linear poly(allylamine) of the formula VII by reaction with a 
cross-linking agent such as L.sup.1 -X-L.sup.2 defined above and then 
carrying out the reductive alkylation with the aldehyde or ketone 
component and reducing agent as defined above. 
It will be understood that in the above mentioned circumstances when no 
self cross-linking occurs during the procedure (a) referred to above, then 
the initially formed, linear (N-alkylated)poly(allylamine) may first be 
alkylated by reaction with the stoichiometric amount of a suitable 
alkylating agent as mentioned above, prior to reaction with the 
cross-linking agent, such as a compound of the formula L.sup.1 -X-L.sup.2 
as defined above. It will also be understood that the precise degree of 
cross-linking required to produce a polymeric allylammonium derivative of 
the invention having the required degree of swelling as defined above will 
also depend on the degree of polymerisation of the linear poly(allylamine) 
of formula VII. 
It will be understood that the above preferred process of the invention may 
readily be modified, for example, by introducing the cross-linking 
structural units of empirical formula IIa as a final step after the 
alkylation procedures. Such a modified process is also provided as a 
further feature of the invention. 
The swelling characteristics of polymeric allylammonium derivatives of the 
invention may be determined in the following manner: 
A sample of the polymeric allylammonium derivative is weighed into a 
graduated centrifuge tube. Sufficient test solvent [water, ethanol or 
0.15M aqueous sodium chloride solution] is then added and the material 
allowed to swell until no perceptible further swelling occurs (this is 
typically about 15 to 60 minutes). The test mixture is then centrifuged 
until sedimentation appears to be complete (about 15 to 30 minutes). The 
volume of sedimented gel polymeric allylammonium derivative is then 
measured and the swelling ratio determined (swollen volume (mL) attained 
per gram sample of polymeric allylammonium derivative). Thus, for example, 
if a 100 mg sample swells to give a swollen volume of 6 mL, the swelling 
ratio is 60. 
As mentioned above, the polymeric allylammonium derivatives of the 
invention possess useful effects in reducing elevated levels in blood 
plasma of low density lipoproteins (LDL) and lipoid components thereof 
such as cholesterol. These effects may be measured by one or more standard 
tests in laboratory animals. 
A first such test is designed to determine the induction of the 
rate-limiting enzyme for cholesterol synthesis [HMG-CoA reductase] in the 
livers of hamsters following dietary administration of a test compound. 
The test has the following basis. 
When bile acids are removed from the gastro-intestinal tract, for example, 
by polymeric materials such as cholestyramine, the liver responds to 
replace the short-fall by upregulating the synthesis of bile acid from 
hepatic cholesterol. Hepatic cholesterol is regulated within narrow limits 
by the induction of specific LDL receptors to acquire LDL-cholesterol from 
the circulation, and also by the upregulation of cholesterol synthesis via 
the induction of enzymes, particularly the rate-limiting enzyme HMG-CoA 
reductase. 
The test procedure is as follows: 
Hamsters (male Syrian, 100-120 g) are acclimatised individually for one 
week in a 14 hour light and 10 hour darkness cycle during which they are 
allowed free access to water and to powdered chow containing 0.75% 
methionine and 10% hydrogenated coconut oil (saturated fat diet). Animals 
are weighed daily for three days prior to dosing with test compound, and 
thereafter throughout the test period. The hamsters are dosed for 7 days 
by mixing the test compound into the diet at the following levels: 
(a) control group--fat diet alone 
(b) test group--4.56 g test compound/kg diet (corresponds to 456 mg/kg/day 
for an animal eating 10 g diet/day) 
(c) positive control group I: cholestyramine 4.56 g/kg diet 
(d) positive control group II: cholestyramine 9.12 g/kg diet. 
On day 7, a cardiac blood sample is taken (under halothane anaesthesia) 
from which plasma cholesterol levels are determined using a standard 
cholesterol assay kit. The animals are sacrificed and a single lobe of 
liver is excised and placed directly into cold (4.degree. C.) sucrose 
buffer containing 50 mM sodium fluoride. Hepatic microsomes are prepared 
according to the method of Ness et al., Biochem. J., 1986, 233, 167-172, 
snap-frozen and stored in liquid nitrogen prior to assay. Microsomal 
HMG-CoA reductase activity is then determined according to a modification 
of the method described by Ness et al., in Lipids, 1987, 22, 409-412, for 
the conversion of .sup.14 C-HMG-CoA to .sup.14 C-mevalonolactone. The 
reaction product is separated from the substrate by mini-column 
chromatography, and the recovery of product is monitored by the inclusion 
of .sup.3 H-mevalonolactone as an internal standard. From these results 
the ratio of activity to that of the positive standard, cholestyramine, is 
then determined. 
In general, the polymeric allylammonium derivatives of the invention show a 
ratio of activity for induction of HMG-CoA reductase of at least 1 (and in 
many cases of 2 or more) at a daily dose of 456 mg/kg (or less) in the 
diet, without any overt toxic or other untoward effects. In addition, the 
polymeric allylammonium derivatives of the invention generally show a 
significant reduction in plasma cholesterol at a daily dose of 456 mg/kg 
(or less) in the diet. 
As an illustration, the polymeric material of Example 3 shows an activity 
ratio of about 2.1 for induction of HMG-CoA reductase at a daily dose in 
the diet of 456 mg/kg. 
The property of the polymeric allylammonium derivatives of the invention in 
reducing elevated blood plasma levels of low density lipoproteins may also 
be demonstrated in other laboratory models well known in the art, for 
example, by measuring the increase in excretion of faecal bile acids and 
related sterols in dogs administered the polymeric allylammonium 
derivatives alone or as a component of their feed. 
It will be understood that for their intended pharmaceutical use, the 
polymeric allylammonium derivatives of the invention will normally be used 
in a specially purified form, and then conveniently be administered in the 
form of a suitable pharmaceutical composition. Therefore, according to 
another aspect of the invention there is provided a pharmaceutical 
composition comprising a polymeric allylammonium derivative D1, D2, D3 or 
D4 as defined above, together with a pharmaceutically acceptable diluent 
or carrier. 
A composition of the invention may be obtained by any of the techniques 
well known to those skilled in the art of pharmacy and include all those 
techniques known for the formulation of analogous polymeric materials for 
human use. 
In general, for liquid compositions, aqueous based pharmaceutically 
acceptable excipients such as water, aqueous ethanol, propylene glycol, 
polyethylene glycol or glycerol or sorbitol solutions are preferred. Such 
formulations may conveniently include flavourings, preservatives and 
sweeteners, such as fruit juices, citric acid, ascorbic acid, aspartame, 
saccharin, sucrose, fructose, invert sugar and cocoa. 
The polymeric allylammonium derivatives of the invention may also be used 
in a form suitable for direct oral administration. Further, because of 
their generally low inherent toxicity, they may also be administered 
orally ad libitum, on a relatively continuous basis, for example, by 
dispersing the polymer in water, other drinks or food. For example, they 
may be presented as a granular formulation for admixture with water or 
other drink to provide a palatable suspension for drinking. 
The polymeric allylammonium derivatives of the invention are preferably 
administered in the form of gelatin capsules or tablets containing the 
derivative in solid particulate form (alone or together with one or more 
other particulate excipients such as lactose or micro-crystalline 
cellulose) or in the form of aqueous or non-aqueous suspensions with a 
suitable suspending agent. Suitable excipients for such compositions 
include, for example, for tablets and capsules, lactose, micro-crystalline 
cellulose, magnesium stearate, polyvinylpyrrolidone, sodium starch 
glycollate and modified starches; and for suspensions, water, ethanol, 
polyethylene glycol, propylene glycol and colloidal silicon dioxide. Any 
of these dosage forms may in addition conveniently contain suitable 
sweetening, preservative and/or flavouring agents, as mentioned above. The 
polymeric allylammonium derivatives of the invention may also be 
conveniently be formulated as a chewable tablet or confectionery bar 
together with the usual binding, flavouring and sweetening agents. 
In general, polymeric allylammonium derivatives of the invention will be 
administered in unit dosage form, each dosage unit containing preferably 
from about 0.5 g to 1.5 g of a polymeric allylammonium derivative D1, D2, 
D3 or D4. 
The daily dosage administered for therapeutic or prophylactic purposes to 
humans will be, for example, a total daily oral dose of between 1 and 10 
g, preferably 1-5 g, the compound being administered up to four times per 
day. However, doses for individual patients will necessarily depend on the 
age and sex of the patient as well as on the extent and severity of the 
disease or adverse condition under treatment. In general a polymeric 
allylammonium derivative of the invention will be administered for a 
continuous period of one month or more sufficient to achieve the required 
reduction in plasma lipid levels. 
The polymeric allylammonium derivatives of the invention may advantageously 
be administered together with (or sequentially to) one or more other 
pharmacological agents known to be useful in the treatment of 
cardiovascular disease, for example, together with agents such as as 
HMG-CoA reductase inhibitors, other hypocholesterolaemic agents such as 
fibrates, for example gemfibrozil, and drugs for the treatment of coronary 
heart disease.

The invention will now be illustrated by the following non-limiting 
Examples in which, unless otherwise stated: 
(1) all operations were carried out at ambient temperature (that is at a 
temperature of about 15.degree.-23.degree. C.; 
(2) yields are given by way of example only and are not necessarily those 
which may be obtained by diligent process development; 
(3) polymeric allylammonium derivatives of the invention are isolated as 
the chloride forms and their chloride content is assessed by argentometric 
analysis; 
(4) the term "poly(allylamine)" is used for convenience and is equivalent 
to the systematic chemical name "poly[1-(aminomethyl)-ethylene]"; 
(5) abbreviated functional names are accorded to the polymer products 
obtained by the exemplified procedures to illustrate the main chemical 
components contained therein; and 
(6) the percentage quaternisation figures are approximate, maximal figures, 
having been obtained by subtraction of the demonstrable amine 
hydrochloride content (measured by potentiometric titration) and are not 
corrected for any residual non-protonated amine groups which may be 
present relating to the approximate total content of quaternary ammonium 
groups. 
EXAMPLE 1 
[This Example describes the preparation of poly(N,N-dimethylallylamine) 
hydrochloride required as a starting material.] 
Poly(allylamine) hydrochloride, (average molecular weight 50000-83000; 10S 
category; obtained from Nitto Boseki Company Ltd., of Fukushima-ken, 
Japan) (46.8 g, 0.5 equivalents) was dissolved in water (100 ml) and the 
mixture cooled to below 10.degree. C. Sodium hydroxide pellets (20 g, 0.5 
mole) were added and the mixture stirred at below 20.degree. C. to form a 
solution. Formic acid (376 ml, excess) was added followed by 37% w/v 
formaldehyde aqueous solution (364 ml, excess). The mixture was heated 
under reflux for 48 hours and then evaporated in vacuo to give a white 
paste. Water (300 ml) was added and the mixture was evaporated in vacuo. 
The solid obtained was slurried in methanol (600 ml) and acidified with 
concentrated hydrochloric acid (100 ml, excess). The liquor was separated 
by filtration from the precipitated sodium chloride, and evaporated in 
vacuo to give a soft white solid. This was dissolved in methanol (200 ml) 
and the solution was drowned out with stirring into acetone (2 L). The 
poly(N,N-dimethylallylamine) hydrochloride formed was separated by 
filtration washed with acetone and dried at 50.degree. C. in vacuo to give 
a white solid (58.7 g); equivalent weight as amine hydrochloride by 
potentiometric titration with N/10 sodium hydroxide: 163. 
EXAMPLE 2 
Trimethylene cross-linked poly(N,N-dimethylallylamine), butyl quaternary 
derivative (48% quaternisation) 
Poly(N,N-dimethylallylamine) hydrochloride (15.6 g, 0.1 equivalents) was 
dissolved in water (75 ml). A solution of sodium hydroxide (4.9 g; 0.12 
mole) in water (25 ml) was then added rapidly to the stirred solution of 
the polyamine hydrochloride at 25.degree.-30.degree. C. The precipitated 
polyamine free base was collected by filtration and washed with warm 
water. The resulting solid was dissolved in ethanol (25 ml) and 
1,3-dibromopropane (1.05 g, 0.01 equivalents) was added. The mixture was 
stirred for 2 hours and then left in a warm oven at 45.degree.-50.degree. 
C. for six days. The resultant gel was slurried in N,N-dimethylformamide 
(DMF) (300 ml) and finely dispersed with an high shear mixer. 
1-Bromobutane (16.4 g, 0.12 equivalents) was then added. The mixture was 
stirred at 30.degree.-40.degree. C. for six days and then added to 
ice-water (1 L) and stirred for 10 minutes. Brine (20% w/v, 200 ml) was 
added. The solid product was removed by filtration, slurried in 0.05N HCl 
(500 ml), collected by filtration and washed successively with 20% w/v 
brine, water (twice), ethanol, methanol and then with ether. This material 
was dried in vacuo at about 50.degree. C. to give the polymer product as a 
white solid in 58% yield; microanalysis, found: C, 49.7%; H, 11.1%; N, 
7.8%; chloride, 22.7%; potentiometric titration showed no free 
hydrochloric acid (HCl), but 52% as amine hydrochloride, indicating that 
the polymer product is 48% quaternised; swelling characteristics: water, 
90; 0.15M NaCl, 33; and ethanol, 33. 
EXAMPLE 3 
Hexamethylene cross-linked poly(N,N-dimethylallylamine), methyl quaternary 
derivative (full quaternisation) 
This polymer was prepared from poly(N,N-dimethylallylamine) hydrochloride 
using a similar procedure to that of Example 2, but replacing the 
1,3-dibromopropane cross-linking agent by 1,6-dibromohexane (0.01 
equivalents per 0.10 equivalents of polyamine) and the 1-bromobutane by 
methyl iodide (0.12 equivalents per 0.10 equivalents of polyamine) and 
using three brine washings to convert iodide to chloride in the end 
product). 
The polymer product was obtained as a white powder (11.9 g); microanalysis, 
found: C, 43.9%; H, 10.6%; N, 7.7%; chloride, 20.9%; potentiometric 
titration with 0.1N NaOH showed no free HCl or amine hydrochloride, 
indicating that the polymer product is essentially fully quaternised; 
swelling characteristics: water, 22; 0.15M NaCl, 12; and ethanol, 11. 
EXAMPLE 4 
2-Hydroxytrimethylene cross-linked poly(N,N-dimethylallylamine), benzyl 
quaternary derivative (89% quaternisation) 
This polymer was prepared from poly(N,N-dimethylallylamine) hydrochloride 
by a similar procedure to that of Example 2 but on twice the scale and 
using 1,3-dichloropropan-2-ol as cross-linking agent and benzyl bromide as 
the quaternising agent. 
The polymer product was obtained as a white powder (27.5 g); microanalysis, 
found: C, 61.4%; H, 9.1%; N, 6.3%; chloride, 16.5%; potentiometric 
titration showed no free HCl, but 11% amine hydrochloride, indicating that 
the polymer is 89% quaternised; swelling characteristics: water, 78; 0.15M 
NaCl, 17; and ethanol, 32. 
EXAMPLE 5 
Trimethylene cross-linked poly(N,N-dimethylallylamine), dodecyl quaternary 
derivative (50% quaternisation) 
This polymer was prepared from poly(N,N-dimethylallylamine) hydrochloride 
by a similar procedure to that of Example 2, but using 1-iodododecane as 
the quaternising agent. 
The polymer product was obtained as a white powder; (11.6 g); 
microanalysis, found: C, 53.9%; H, 11.1%; N, 5.9%; chloride, 16.1%; 
potentiometric titration showed no free HCl, but 50% amine hydrochloride, 
indicating that the polymer product is 50% quaternised; swelling 
characteristics: water, 5; 0.15M NaCl, 5; and ethanol, 22. 
EXAMPLE 6 
Trimethylene cross-linked poly(N,N-dimethylallylamine), octyl quaternary 
derivative (42% quaternisation) 
This polymer was prepared from poly(N,N-dimethylallylamine) hydrochloride 
by a similar procedure to that of Example 2, but carrying out the 
quaternisation by heating at reflux for 48 hours in ethanol and using 
1-bromooctane (1.2 moles per equivalent of amine) as quaternising agent. 
The polymer product was obtained as a white powder (4.2 g); microanalysis, 
found: C, 47.5%; H, 10.4%; N, 6.9%; chloride, 21.2%; potentiometric 
titration showed no free HCl, but 58% amine hydrochloride, indicating that 
the polymer product is 42% quaternised; swelling characteristics: water, 
260; 0.15M NaCl, 32; and ethanol, 65. 
EXAMPLES 7-18 
Using a similar procedure to that described in Example 2 the following 
polymer products were obtained: 
(Example 7) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), methyl quaternary 
derivative (89% quaternisation) 
This polymer product was obtained using iodomethane as quaternising agent 
in the second stage (1 mole per equivalent of amine) which was performed 
in ethanol (400 ml per 0.1 equivalent amine) over 6 days. The polymer 
product was obtained in 30% yield; microanalysis, found: C,42.3%; H,10.3%; 
N,7.8%. chloride, 20.8%; potentiometric titration showed no free HCl, but 
11% amine hydrochloride, indicating that the product is 89% quaternised; 
swelling characteristics: water, 140; 0.15M NaCl, 28; and ethanol, 42. 
(Example 8) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), butyl quaternary 
derivative (43% quaternisation) 
This polymer product was obtained essentially as described in Example 2, 
except that the starting poly(N,N-dimethylallylamine) hydochloride was 
obtained as in Example 1 but using a different sample of poly(allylamine) 
hydrochloride (average molecular weight about 10000; 3S category, obtained 
from Nitto Boseki Company Ltd.). The polymer product was obtained in 37% 
yield; microanalysis, found: C,45.2%; H,10.7%; N,7.9%; chloride, 22.0%; 
potentiometric titration showed no free HCl, but 57% amine hydrochloride, 
indicating that the product is 43% quaternised; swelling characteristics: 
water, 65; 0.15M NaCl, 19; and ethanol, 19. 
(Example 9) 
Hexamethylene cross-linked poly(N,N-dimethylallylamine), butyl quaternary 
derivative (38% quaternisation) 
This polymer product was obtained by replacing the 1,3-dibromopropane 
cross-linking agent with 1,6-dibromohexane. The polymer product was 
obtained in 72% yield; microanalysis, found: C,47.7%; H,11.0%; N,7.7%; 
chloride, 21.5%; potentiometric titration showed no free HCl, but 62% 
amine hydrochloride, indicating that the product is 38% quaternised; 
swelling characteristics: water, 30; 0.15M NaCl, 25; and ethanol, 14. 
(Example 10) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), butyl quaternary 
derivative (53% quaternisation) 
This polymer product was obtained by replacing 1-bromobutane with 
1-iodobutane as quaternising agent. The polymer product was obtained in 
59% yield; microanalysis, found: C,49.3%; H,10.5%; N,7.5%; chloride, 
20.9%; potentiometric titration showed no free HCl, but 47% amine 
hydrochloride, indicating that the product is 53% quaternised; swelling 
characteristics: water, 85; 0.15M NaCl, 30; and ethanol, 25. 
(Example 11) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), dodecyl quaternary 
derivative (38% quaternisation) 
This polymer product was obtained using poly(N,N-dimethylallylamine) 
hydrochloride obtained from low molecular weight 
poly(N,N-dimethylallylamine) obtained as mentioned in Example 8, and 
replacing 1-bromobutane by 1-bromododecane as quaternising agent. The 
polymer product was obtained in 57% yield; microanalysis, found: C,53.6%; 
H,11.5%; N,6.8%; chloride, 18.7%; potentiometric titration showed no free 
HCl, but 62% amine hydrochloride, indicating that the product is 38% 
quaternised; swelling characteristics: water 9; 0.15M NaCl, 5; and 
ethanol, 32. 
(Example 12) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), dodecyl quaternary 
derivative (36% quaternisation) 
This polymer product was obtained by replacing 1-bromobutane by 
1-bromododecane as quaternising agent. The polymer product was obtained in 
57% yield; microanalysis, found: C,50.0%; H,10.7%; N,6.8%; chloride, 
19.5%; potentiometric titration showed no free HCl, but 64% amine 
hydrochloride, indicating that the product is 36% quaternised; swelling 
characteristics: water, 20; 0.15M NaCl, 5; ethanol, 29. 
(Example 13) 
2-Hydroxytrimethylene cross-linked poly(N,N-dimethylallylamine), octyl 
quaternary derivative (42% quaternisation) 
This polymer product was obtained by using 1,3-dichloropropan-2-ol instead 
of 1,3-dibromopropane as cross-linking agent, and 1-bromo-octane instead 
of 1-bromobutane as quaternising agent. The quaternisation stage was 
carried out at ambient temperature for 4 days followed by 6 days at 
40.degree. C. The polymer product was obtained in 35% yield; 
microanalysis, found: C,43.8%; H,9.9%; N,6.4%; chloride, 18.1%; 
potentiometric titration showed no free HCl, but 58% amine hydrochloride, 
indicating that the product is 42% quaternised; swelling characteristics: 
water, 72; 0.15M NaCl, 14; and ethanol, 18. 
(Example 14) 
Hexamethylene cross-linked poly(N,N-dimethylallylamine), octyl quaternary 
derivative (23% quaternisation) 
This polymer product was obtained by using 1,6-dibromohexane as 
cross-linking agent and 1-bromo-octane as quaternising agent. The 
quaternisation stage was conducted in ethanol (400 ml per 0.1 equivalent 
of poly(N,N-dimethylallylamine) starting material) at reflux for 48 hours. 
The polymer product was obtained in 37% yield; microanalysis, found: 
C,48.6%; H,10.5%; N,7.2%; chloride, 20.4%; potentiometric titration showed 
no free HCl, but 77% amine hydrochloride, indicating that the product is 
23% quaternised; swelling characteristics: water, 120; 0.15M NaCl, 22; and 
ethanol 37. 
(Example 15) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), carbamoylmethyl 
quaternary derivative (87% quaternisation) 
This polymer product was obtained by replacing 1-bromobutane with 
1-iodoacetamide (0.2 moles per equivalent of poly(N,N-dimethylallylamine) 
starting material) as quaternising agent. The polymer product was obtained 
in 65% yield; microanalysis, found: C,43.3%; H,9.1%; N,12.0%; chloride, 
18.7%; potentiometric titration showed no free HCl, but 13% amine 
hydrochloride, indicating that the product is 87% quaternised; swelling 
characteristics: water, 50; 0.15M NaCl, 17; and ethanol, 4. 
(Example 16) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), 2-hydroxyethyl 
quaternary derivative (51% quaternisation) 
This polymer product was obtained by replacing 1-bromobutane with 
2-iodoethanol (0.2 moles per 0.1 equivalent of 
poly(N,N-dimethylallylamine) starting material) as quaternising agent. The 
polymer product was obtained in 58% yield; microanalysis, found: C,45.7%; 
H,10.5%; N,8.3%; chloride, 21.9%; potentiometric titration showed no free 
HCl, but 49% amine hydrochloride; indicating that the product is 51% 
quaternised; swelling characteristics: water, 60; 0.15M NaCl, 24; and 
ethanol, 10. 
(Example 17) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), butyl quaternary 
derivative (20% quaternisation) 
This polymer product was obtained by replacing 1-bromobutane with 
1-iodobutane (0.02 moles per 0.1 equivalents of 
poly(N,N-dimethylallylamine) starting material) as quaternising agent in 
DMF (200 ml per 0.1 equivalents polyamine). The polymer product was 
obtained in 43% yield; microanalysis, found: C,45.8%; H,12.4%; N,8.6%; 
chloride, 22.9%; potentiometric titration showed no free HCl, but 80% 
amine hydrochloride, indicating that the product is 20% quaternised; 
swelling characteristics: in water, 240; 0.15M NaCl, 48; and ethanol, 80. 
(Example 18) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), butyl quaternary 
derivative (37% quaternisation) 
This polymer product was obtained by replacing 1-bromobutane with 
1-iodobutane (0.04 moles per 0.1 equivalents poly(N,N-dimethylallylamine) 
starting material) as quaternising agent in DMF (200 moles per 0.1 
equivalents polyamine). The polymer product was obtained in 40% yield; 
microanalysis, found: C,48.1%; H,12.3%; N,8.0%; chloride, 21.0%; 
potentiometric titration showed no free HCl, but 63% amine hydrochloride, 
indicating that the product is 37% quaternised; swelling characteristics: 
water, 240; 0.15M NaCl, 40; and ethanol; 60. 
EXAMPLE 19 
[This Example describes the production of self cross-linked 
poly(N-ethylallylamine) hydrochloride which is used as a starting 
material.] 
Poly(allylamine) hydrochloride (category 3S from Nitto Boseki Company Ltd.; 
100 g, 1 equivalent) was added to a solution of sodium hydroxide (40 g, 1 
mole) in methanol (1 L) and the mixture was stirred at 
40.degree.-50.degree. C. for 5 hours and then at ambient temperature for 
16 hours. The mixture was reduced in volume by evaporation in vacuo and 
solid removed by filtration to give a solution (245 g) of poly(allylamine) 
free base which analysed as 3.2N by potentiometric titration with 
hydrochloric acid and therefore contained 0.78 equivalents of amine. 
A portion of this solution (63 g, 0.2 equivalents) was diluted with ethanol 
(30 ml) and cooled to below 20.degree. C. Acetaldehyde (8.8 g, 0.2 mole) 
was added dropwise over 5 minutes, whilst stirring and keeping the mixture 
below 30.degree. C. During this procedure the mixture gelled, and it was 
left at 20.degree.-30.degree. C. for a further 15 minutes. The gel was 
then ground using a mortar and pestle, and mixed with ethanol (50 ml) to 
form a paste. Sodium borohydride (11.3 g, 0.3 mole) was added to the paste 
in portions over 20 minutes, with stirring and keeping the reaction 
temperature below 30.degree. C. The mixture was stirred at ambient 
temperature for 16 hours and then thoroughly washed with water (about 5 
L). The gel was then acidified with hydrochloric acid (1N, about 1 L) and 
broken up using an high shear mixer. It was then washed acid free with 
water, shrunk and dehydrated by further washes with ethanol and ether, and 
then dried in vacuo to give self cross-linked poly(N-ethylallylamine) 
hydrochloride, as a powder, 21.8. g; microanalysis, found C, 45.9%; H, 
10.5%; N, 10.5%; chloride, 25.3%. 
EXAMPLE 20 
Self cross-linked poly(N-ethylallylamine), dimethyl quaternary derivative 
(72% quaternisation) 
A solution of sodium hydroxide (6.4 g, 0.16 mole) in methanol (26 g) was 
added to a stirred mixture of self cross-linked poly(N-ethylallylamine) 
hydrochloride (12.1 g, 0.075 equivalents) in ethanol (200 ml). Iodomethane 
(42.6 g, 0.3 mole) was then added and the mixture was stirred for 6 days 
at 30.degree.-40.degree. C. It was then added to ice-water (500 ml). The 
gelatinous product was collected by filtration, washed thoroughly with 
water, acidified by washing with hydrochloric acid (1N, 540 ml), again 
washed thoroughly with water, and then stirred in brine [obtained from 
NaCl (150 g) in H.sub.2 O (500 ml)] for 16 hours to convert iodide to 
chloride. It was then thoroughly washed successively with water, ethanol 
and ether and then dried in vacuo to give the title polymer product as a 
solid, (12.8 g); microanalysis: C, 49.2%; H 11.1%; N, 8.4%; chloride, 
21.8%; potentiometric titration showed no free HCl, but 28% amine 
hydrochloride, indicating that the product is 72% quaternised; swelling 
characteristics: water, 28; 0.15M NaCl, 11, and ethanol, 10. 
EXAMPLE 21 
Self cross-linked poly(N-butylallylamine), dimethyl quaternary derivative 
(67% quaternisation) 
A sample of self cross-linked poly(N-butylallylamine) hydrochloride was 
prepared using an analogous procedure to that in Example 19, but replacing 
acetaldehyde by butyraldehyde in the reductive alkylation stage. This 
starting polyamine derivative was then alkylated with iodomethane using a 
similar procedure to Example 20, with sufficient brine washing in the 
work-up procedure to remove all iodide ion from the product, which was 
obtained in 34% yield; microanalysis: C, 49.2%; H, 10.2%; N, 6.5%; 
chloride, 18.6%; potentiometric titration showed no free HCl, but 33% 
amine hydrochloride, indicating that the product is 67% quaternised; 
swelling characteristics: water, 50; 0.15M NaCl, 18; and ethanol, 21. 
EXAMPLE 22 
Self cross-linked poly(N-octylallylamine) dimethyl quaternary derivative 
(71% quaternisation) 
A sample of self cross-linked poly(N-octylallylamine) hydrochloride was 
prepared by an analogous procedure to that in Example 19, but replacing 
acetaldehyde by octanal in the reductive alkylation stage. This polyamine 
derivative was then alkylated with iodomethane using a similar procedure 
to Example 20, with sufficient brine washing in the work-up procedure to 
remove all iodide ion from the product, which was obtained in 45% yield; 
microanalysis: C, 60.2%; H, 11.7%; N, 5.0%; chloride, 12.6%, 
potentiometric titration showed no free HCl, but 29% amine hydrochloride, 
indicating that the product is 71% quaternised; swelling characteristics: 
water, 2; 0.15M NaCl, 2; and ethanol, 12. 
EXAMPLE 23 
[This Example describes the preparation of dodecamethylene cross-linked 
poly(allylamine) required as a starting material.] 
A solution of sodium hydroxide (64 g, 1.6 mole) in methanol (200 ml) was 
added slowly to a stirred solution of poly(allylamine) hydrochloride 
(category 10S; from Nitto Boseki Company Ltd.; 200 g, 2 equivalents) in 
water (100 g). The mixture was stirred for a further 30 minutes. 
1,12-Dibromododecane (16.4 g, 0.05 mole) and then DMF (60 ml) were added 
and the mixture stirred for one hour. It was then stirred at 60.degree. C. 
until it gelled. It was then left standing at this temperature for a total 
of 24 hours. The gelatinous mixture was basified by dispersal in a 
solution of sodium hydroxide (17.6 g, 0.44 mole) in water (about 3 L) 
using an high shear mixer. The gel product obtained was collected by 
filtration and washed alkali free with water. It was then stirred first 
with acetone and then with ether, collected by filtration and dried in 
vacuo to give the dodecamethylene cross-linked poly(allylamine) (147 g); 
potentiometric titration (involving back-titration of excess acid after 
soaking an aliquot of the product in hydrochloric acid for several hours) 
indicated an equivalent weight, as amine, of 98. 
EXAMPLE 24 
[This Example describes the preparation of dodecamethylene cross-linked 
poly(N-octylallylamine) hydrochloride required as a starting material.] 
Dodecamethylene cross-linked poly(allylamine) (28.5 g, 0.3 equivalents) 
(prepared as described in Example 23) was dispersed in ethanol (210 ml) 
and left to swell overnight. Ethanol (390 ml) and octanal (38.5 g, 0.3 
mole) were then added, keeping the reaction temperature below 30.degree. 
C. The mixture was stirred at ambient temperature for 15 minutes. Sodium 
borohydride (17.0 g, 0.45 mole) was then added slowly, over 20 minutes, 
keeping the reaction temperature below 30.degree. C. Stirring was 
continued at this temperature for 2 hours and then for 16 hours at ambient 
temperature. The mixture was then added to water (1 L). The gelatinous 
product was collected by filtration, washed thoroughly with water, 
acidified in aqueous ethanol (50:50 v/v, 1 L) with concentrated 
hydrochloric acid (60 ml), thoroughly washed with water and then dried by 
washing with ethanol and ether before being dried in vacuo to give 
dodecamethylene cross-linked poly(N-octylallylamine) hydrochloride (61.8 
g); microanalysis: C, 61.2%; H, 11.9%; N, 6.8%; chloride, 17.4%; swelling 
characteristics water, 3; 0.15M NaCl,3; and ethanol, 7. 
EXAMPLE 25 
Dodecamethylene cross-linked poly(N-octylallylamine), dimethyl quaternary 
derivative (66% quaternisation) 
Dodecamethylene cross-linked poly(N-octylallylamine) hydrochloride (22.0 g, 
0.1 equivalent) (prepared as described in Example 24) was alkylated with 
iodomethane using a similar procedure to that in Example 20, with repeated 
washings with ethanolic hydrochloric acid (about 2N) until the product was 
iodide free. The polymer product was obtained in 84% yield; microanalysis: 
C, 62.0%; H, 13.2%; N, 5.4%; chloride, 13.6%; potentiometric titration 
showed no free HCl, but 34% amine hydrochloride, indicating that the 
product is 66% quaternised; swelling characteristics: water, 2; 0.15M 
NaCl, 2; and ethanol, 7. 
EXAMPLE 26 
Dodecamethylene cross-linked polT(N-dodecylallylamine), dimethyl quaternary 
derivative (37% quaternisation) 
Dodecamethylene cross-linked poly(allylamine), (5 mole % cross-linked: 
prepared by a similar procedure to that described in Example 23) was 
converted to the dodecyl derivative by an analogous reductive alkylation 
to that of Example 24, but using dodecanal as the aldehyde component. The 
initial product, a poly(N-dodecylallylamine) gel, was methylated by a 
procedure similar to that of Example 20, using 2.5 mole of iodomethane and 
2.0 mole of sodium hydroxide per equivalent of amine. The title polymer 
product was obtained in 77% yield; microanalysis, found: C,58.4%; H,11.7%; 
N,4.0%; chloride, 13.4%; potentiometric titration showed no free HCl, but 
63% amine hydrochloride, indicating that the product is 37% quaternised; 
swelling characteristics: water, 4; 0.15M NaCl, 4; and ethanol, 4. 
EXAMPLE 27 
Trimethylene cross-linked poly(N,N-dimethylallylamine), 2-methylpropyl 
quaternary derivative (35% quaternisation) 
This polymer product was obtained using a similar procedure to that 
described in Example 2, but 1-iodo-2-methylpropane was used as 
quaternising agent in the second stage (2 mole per equivalent of amine). 
The polymer product was obtained in 69% yield; microanalysis, found: 
C,47.8%; H,10.7%; N,8.9%; chloride, 22.1%; potentiometric titration showed 
no free HCl, but 65% amine hydrochloride, indicating that the product is 
35% quaternised; swelling characteristics: water, 66; 0.15M NaCl, 19; and 
ethanol, 17. 
EXAMPLE 28 
Trimethylene cross-linked poly(N-butylallylamine), butyl/methyl quaternary 
derivative (40% quaternisation) 
Trimethylene cross-linked poly(N-butylallylamine) gel was prepared by a 
similar procedure to Example 24, but replacing 1,12-dibromododecane by 
1,3-dibromopropane in the cross-linking stage and octanal by butyraldehyde 
in the reductive alkylation stage. A portion of this gel (33.0 g, derived 
from 0.2 equivalents original poly(allylamine) gel) was then slurried in 
ethanol (350 ml), converted to free base form by addition of methanolic 
sodium hydroxide (8.6 g, 0.215 mole, in 27 g methanol), and then alkylated 
by reaction with 1-iodobutane (36.8 g, 0.2 mole) at 40.degree. C. for 2 
days. The mixture was then re-basified with methanolic sodium hydroxide 
[33 g containing NaOH (8.0 g, 0.2 mole)] and alkylated with further 
1-iodobutane (55.2 g, 0.3 mole) at 40.degree. C. for 2 days. The 
gelatinous product was collected by filtration, washed well with ethanol, 
acidified with hydrochloric acid (1N, about 500 ml), washed thoroughly 
with water, 20% w/v brine (until iodide free), then with water, ethanol 
and ether. The material obtained was dried in vacuo to give as the 
intermediate polymer product poly(N-butylallylamine), butyl 
alkylated/quaternised, in a yield of 37.4 g; microanalysis, found: 
C,52.4%; H,10.8%; N,6.6%; chloride, 16.7%; potentiometric titration showed 
no free HCl, but 86% amine hydrochloride, indicating that the product is 
14% quaternised; swelling characteristics: water, 20; 0.15M NaCl, 13; and 
ethanol, 13. 
A half portion of this product (18.7 g, derived from 0.1 equivalents of 
original poly(allylamine) gel) was stirred in ethanol (1 L) and methanolic 
sodium hydroxide [16.5 g containing 0.1 mole (4.0 g) NaOH was added]. The 
mixture was stirred for 10 minutes. The gel was removed by filtration, 
washed thoroughly with ethanol, and then stirred in ethanol (200 ml) and 
reacted with iodomethane (21.3 g, 0.15 mole) at 40.degree. C. for 3 days. 
The mixture was added to water (1 L). The gelatinous solid obtained was 
collected by filtration and washed thoroughly with water. It was the 
acidified with hydrochloric acid (1N, 600 ml), and washed thoroughly 
successively with water, 20% w/v brine (until iodide free), water, ethanol 
and then ether. It was then dried in vacuo to give the title polymer 
product (19.0 g) alkylated and quaternised with butyl and methyl; 
microanalysis, found: C,53.2%; H,10.9%; N,6.2%; chloride, 15.5%; 
potentiometric titration showed no free HCl, but 60% amine hydrochloride, 
indicating that the product is 40% quaternised; swelling characteristics: 
water, 22; 0.15M NaCl, 13; and ethanol, 13. 
EXAMPLE 29 
Dodecamethylene cross-linked poly(N-butylallylamine), butyl/methyl 
quaternary derivative (59% quaternisation) 
This polymer product was prepared by a similar procedure to that in Example 
28, but replacing 1,3-dibromopropane by 1,12-dibromododecane (0.025 mole 
per equivalent of amine) in the cross-linking stage. The polymer product 
was obtained in 86% yield; microanalysis, found: C,56.4%; H,11.1%; N,6.5%, 
chloride, 13.6%; potentiometric titration showed no free HCl, but 41% 
amine hydrochloride, indicating that the product is 59% quaternised; 
swelling characteristics: water, 7; 0.15M NaCl, 7; and ethanol,7. 
EXAMPLE 30 
Trimethylene cross-linked poly(N-dodecylallylamine), dimethyl quaternary 
derivative (58% quaternisation) 
This polymer product was prepared by a similar procedure to that in Example 
26, but using only 2.5 mole % (based on amine) of 1,3-dibromopropane as 
cross-linking agent in the first stage, and 3.0 moles of iodomethane and 
2.0 moles of sodium hydroxide per equivalent of poly(N-dodecylallylamine) 
gel in the methylation stage. The polymer product was obtained in 97% 
yield; microanalysis, found: C,64.2%; H,12.3%; N,5.5%; chloride, 12.7%, 
potentiometric titration showed no free HCl, but 42% amine hydrochloride, 
indicating that the product is 58% quaternised; swelling characteristics: 
ethanol, 8; [Note: not wetted by water or 0.15M NaCl]. 
EXAMPLES 31-35 
Using a similar procedure to that described in Example 2 the following 
polymer products were obtained: 
(Example 31) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), methyl quaternary 
derivative (100% quaternisation) 
This polymer was obtained using iodomethane as quaternising agent in the 
second stage (1.5 mole per equivalent of amine) which was performed in DMF 
(250 ml per 0.1 equivalent of amine) over 6 days. The polymer product was 
obtained in 56% yield; microanalysis, found: C, 45.3%; H, 11.3%; N, 8.3%; 
chloride 21.8%; potentiometric titration showed no free HCl and no amine 
hydrochloride, indicating that the product is 100% quaternised; swelling 
characteristics: water 56; 0.15M NaCl 20; and ethanol, 22. 
(Example 32) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), methyl quaternary 
derivative (100% quaternisation) 
This polymer product was obtained using 2.5 mole % (based on amine) of 
1,3-dibromopropane as cross-linking agent in the first stage, and 
iodomethane as quaternising agent in the second stage (1.5 mole per 
equivalent of amine) which was performed in DMF (250 ml per 0.1 equivalent 
of amine) over 6 days. The polymer product was obtained in 50% yield; 
microanalysis, found: C, 47.4%; H, 12.2%; N, 8.7%; chloride 22.5%; 
potentiometric titration showed no free HCl and no amine hydrochloride, 
indicating that the product is 100% quaternised; swelling characteristics: 
water, 180; 0.15M NaCl, 32; and ethanol, 48. 
(Example 33) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), propyl quaternary 
derivative (61% quaternisation) 
This polymer product was obtained using 1-iodopropane as quaternising agent 
in the second stage (2 mole per equivalent of amine) in DMF (135 ml per 
0.1 equivalent of amine). The polymer product was obtained in 61% yield; 
microanalysis, found: C, 50.1%; H, 10.7%; N, 8.1%; chloride, 21.4%; 
potentiometric titration showed no free HCl, but 39% amine hydrochloride, 
indicating that the product is 61% quaternised; swelling characteristics: 
water, 160; 0.15M NaCl, 28; and ethanol, 44. 
(Example 34) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), pentyl quaternary 
derivative (58% quaternisation) 
This polymer product was obtained using 1-iodopentane as quaternising agent 
in the second stage (2 mole per equivalent of amine) in DMF (135 ml per 
0.1 equivalent of amine). The polymer product was obtained in 56% yield; 
microanalysis, found: C, 51.0%; H,10.8%; N, 7.1%; chloride, 19.1%; 
potentiometric titration showed no free HCl but 42% amine hydrochloride, 
indicating that the product is 58% quaternised; swelling characteristics: 
water, 140; 0.15M NaCl 25; and ethanol, 36. 
(Example 35) 
Trimethylene cross-linked poly(N,N-dimethylallylamine), methyl quaternary 
derivative (94% quaternisation) 
This polymer product was prepared from poly(N,N-dimethylallylamine) 
hydrochloride using a similar procedure to that of Example 2, but using 
0.015 equivalents of the 1,3-dibromopropane cross-linking agent per 0.1 
equivalent of polyamine and replacing the 1-bromobutane by iodomethane in 
the second stage (0.2 mole per 0.1 equivalent of amine). The polymer 
product was obtained in 62% yield; microanalysis, found: C, 45.0%; H, 
10.5%; N, 8.0%; chloride, 20.7%; potentiometric titration showed no free 
HCl, but 6% amine hydrochloride, indicating that the product is 94% 
quaternised; swelling characteristics: water, 16; 0.15M NaCl, 8; and 
ethanol, 8. 
EXAMPLE 36 
Self cross-linked poly(N-octylallylamine) dimethyl quaternary derivative 
(66% quaternisation) 
A sample of self cross-linked poly(N-octylallylamine) hydrochloride was 
prepared by an analogous procedure to that in Example 19, but replacing 
acetaldehyde by octanal in the reductive alkylation stage. This polyamine 
was then alkylated with iodomethane in DMF (125 ml per equivalent of 
amine) using a similar procedure to Example 20, but washing with 10% 
ethanolic hydrochloric acid rather than brine to remove all iodide ion 
from the product, which was obtained in 65% yield; microanalysis, found: 
C, 61.3%; H, 11.8%; N, 5.9%; chloride, 13.5%; potentiometric titration 
showed no free HCl, but 34% amine hydrochloride, indicating that the 
product is 66% quaternised; swelling characteristics: ethanol, 7; [note: 
not wetted by water or 0.15M NaCl]. 
EXAMPLE 37 
Trimethylene cross-linked poly(N,N-dimethylallylamine), butyl/methyl 
quaternary derivative (87% quaternisation) 
Partially butylated, trimethylene cross-linked poly(N,N-dimethylallylamine) 
gel was obtained using a similar procedure to Example 2 with 1-iodobutane 
(0.05 mole per 0.1 equivalent of polyamine) as quaternising agent in DMF 
(135 ml per 0.1 equivalent of amine). This gel was converted to the free 
base form by slurrying in 0.1N sodium hydroxide (1.5 L per 0.1 equivalent 
of amine) and washing alkali free with ethanol. The gel was then slurried 
in DMF (135 ml per 0.1 equivalent of amine starting material) and further 
alkylated by reaction with iodomethane (0.13 mole per 0.1 equivalent of 
amine starting material) at 40.degree. C. for 2 days. The gelatinous 
product was collected by filtration and washed thoroughly with water. It 
was then slurried in ethanolic hydrochloric acid (100 ml 10N hydrochloric 
acid and 400 ml ethanol per 0.1 equivalent of amine starting material), 
filtered, and re-treated with the ethanolic hydrochloric acid. It was then 
thoroughly washed with water, ethanol, acetone and diethyl ether, and 
dried in vacuo. The polymer was obtained in 54% yield: microanalysis, 
found: C, 48.5%; H, 12.3%; N, 7.6%; chloride, 22.2% potentiometric 
titration should no free HCl, but 13% amine hydrochloride, indicating that 
the product is 87% quaternised; swelling characteristics: water, 100; 
0.15M NaCl, 25; and ethanol, 20. 
EXAMPLE 38 
Trimethylene cross-linked poly(N,N-dimethylallylamine), octyl/methyl 
quaternary derivative (90% quaternisation) 
The polymer was obtained using a similar procedure to that described in 
Example 37 but 1-iodobutane was replaced by 1-iodooctane as quaternising 
agent in the first alkylation stage (0.025 mole per 0.1 equivalent of 
amine starting material). The polymer product was obtained in 44% yield; 
microanalysis, found: C, 47.6%; H, 10.6%; N, 7.0%; chloride, 19.1%; 
potentiometric titration showed no free HCl, but 10% amine hydrochloride, 
indicating that the product is 90% quaternised; swelling characteristics: 
water, 140; 0.15M NaCl, 25; and ethanol, 45. 
EXAMPLE 39 
[This example describes the preparation of 2-hydroxypropylene cross-linked 
poly(allylamine) required as a starting material] 
A solution of sodium hydroxide (32 g, 0.8 mole) in water (37 ml) was added 
slowly to a stirred mixture of poly(allylamine) hydrochloride (category 
10S: from Nitto Boseki Company Ltd; 100 g, 1 equivalent) water (300 ml) 
and ethanol (100 ml). 1,3-Dichloropropan-2-ol (6.5 g, 0.05 mole) was then 
added and the mixture heated to 55.degree. C. and stirred until it gelled. 
It was then left standing at this temperature for a total of 6 hours, and 
for 16 hours further at ambient temperature. The gelatinous mixture was 
basified by dispersal in a solution of sodium hydroxide (20 g, 0.5 mole) 
in water (about 2 L) using an high shear mixer. The gel product was 
collected by filtration and washed alkali free with water. It was then 
washed with ethanol, collected by filtration and dried in vacuo to give 
the 2-hydroxypropylene cross-linked poly(allylamine) (72 g); 
potentiometric titration (involving back titration of excess acid after 
soaking an aliquot of the product in hydrochloric acid for several hours) 
indicated an equivalent weight, as amine, of 90. 
EXAMPLE 40 
2-Hydroxypropylene cross-linked poly(N-cyclohexylallylamine), dimethyl 
quaternary derivative (46% quaternisation) 
2-Hydroxypropylene cross-linked poly(allylamine) (9 g, 0.1 equivalent) 
(prepared as described in Example 39) was reductively alkylated using a 
similar procedure to Example 24, but using cyclohexanone as the 
aldehyde/ketone component. The reaction product, a 
poly(N-cyclohexylallylamine) gel was collected by filtration, washed 
thoroughly with water and then ethanol, then slurried in a solution of 
sodium hydroxide (6.0 g, 0.15 mole) in ethanol (400 ml) and water (200 
ml). The free base gel was collected by filtration and washed alkali free 
with water, then thoroughly washed with ethanol. It was sucked dry and 
then slurried in DMF (200 ml). Iodomethane (56.8 g, 0.4 mole) was added 
and the mixture stirred at 45.degree. C. for 6 days. The gel product 
obtained was collected and washed thoroughly with ethanol. It was then 
converted to the chloride form by repeated slurrying in a solution of 
hydrochloric acid (about 100 ml cHCl) in ethanol (500 ml) and water (200 
ml) until the washings were iodide-free. It was then washed with water 
until acid-free, washed thoroughly with ethanol, and dried in vacuo to 
give the polymer product (19.0 g), microanalysis, found: C, 50.0%; H, 
10.1%; N, 6.6%; chloride, 15.4%; potentiometric titration showed no free 
HCl, but 54% amine hydrochloride, indicating that the product is 46% 
quaternised; swelling characteristics: water, 19; 0.15M NaCl, 12; and 
ethanol, 11. 
EXAMPLE 41 
2-Hydroxypropylene cross-linked poly(N-3-methylbutylallylamine), dimethyl 
derivative (57% quaternisation) 
This polymer product was prepared by a similar procedure to that of Example 
40 but replacing cyclohexanone by 3-methylbutanal in the reductive 
alkylation stage. The polymer product was obtained in 79% yield; 
microanalysis, found: C, 55.8%; H, 8.4%; N, 6.6%; chloride, 14.6%; 
potentiometric titration showed no free HCl, but 43% amine hydrochloride, 
indicating that the product is 57% quaternised; swelling characteristics: 
water, 21; 0.15M NaCl, 12; and ethanol, 11. 
EXAMPLE 42 
Trimethylene cross-linked poly(N,N-dimethylallylamine), hexyl quaternary 
derivative (57% quaternisation) 
This polymer product was obtained by an analogous procedure to that 
described in Example 2, using 1-iodohexane as quaternising agent in the 
second stage (2 mole per equivalent of amine) in DMF (135 mL per 0.1 
equivalent of amine). The polymer product was obtained in 57% yield; 
microanalysis, found: C, 53.2%; H, 11.0%; N, 6.7%; chloride, 19.3%; 
potentiometric titration showed no free HCl, but 43% of amine 
hydrochloride, indicating that the product is 57% quaternised; swelling 
characteristics: water, 132; 0.15M NaCl, 28; and ethanol, 34. 
EXAMPLE 43 
[This example describes the preparation of trimethylene cross-linked 
poly(allylamine) required as a starting material.] 
A solution of sodium hydroxide (64 g, 1.6 mole) in methanol (200 g) was 
added slowly to a solution of poly(allylamine) hydrochloride (category 
10S; from Nitto Boseki Company Ltd; 200 g, 2 equivalents) in water (100 
g), followed by ethanol (60 mL). The mixture was stirred for one hour 
until homogeneous. 1,3-dibromopropane (10.1 g, 0.05 mole) was then added 
and the mixture heated to 60.degree. C. and stirred until it gelled. It 
was left standing at this temperature for 1 day then worked-up by a 
similar procedure to that of Example 39. The title product was obtained as 
a white powder (159.3 g); potentiometric titration (involving 
back-titration of excess acid after soaking an aliquot of the product in 
hydrochloric acid for several hours) indicated an amine equivalent weight 
of 95. 
EXAMPLE 44 
[This example describes the preparation of trimethylene cross-linked 
poly(N-ethylallylamine) hydrochloride required as a starting material.] 
Trimethylene cross-linked poly(allylamine), prepared as described in 
Example 43 was reductively alkylated by a similar procedure to that 
described in Example 24 but using acetaldehyde as aldehyde component and 
with a reduced charge of ethanol (a total of 280 mL per 0.3 equivalent of 
amine starting material). The polymer product was obtained in 98% yield, 
microanalysis, found: C, 50.2%; H, 11.8%; N, 9.3%; chloride, 21.7% 
potentiometric titration showed no free HCl, and an equivalent weight, as 
amine hydrochloride, of 149; swelling characteristics: water, 27; 0.15M 
NaCl, 16; and ethanol, 11. 
EXAMPLE 45 
Trimethylene cross-linked poly(N-methyl-N-ethylallylamine), ethyl 
quaternary derivative (23% quaternisation) 
Trimethylene cross-linked poly(N-ethylallylamine) hydrochloride, prepared 
as described in Example 44 (32.8 g, 0.22 equivalents) was suspended in 
water (500 mL). A solution of sodium hydroxide (8.8 g, 0.22 mole) in water 
(11 mL) was then rapidly added to the stirred suspension of the polyamine 
and stirring was continued for 30 minutes. The polyamine free base was 
collected by filtration and washed alkali-free with water. The resulting 
solid was added with stirring to formic acid (400 mL, excess), followed by 
37% formaldehyde aqueous solution (400 mL, excess). The mixture was heated 
under reflux for 30 hours then cooled and the solid collected by 
filtration. It was washed with 10% w/v brine then slurried in a solution 
of sodium hydroxide (10 g, 0.25 mole) in water (500 mL). The solid was 
collected by filtration and washed with ethanol (about 1 L), 0.5N NaOH 
(500 mL) then alternately with ethanol and with water (about 500 mL) until 
alkali free, ending with an ethanol wash. The solid was sucked dry then 
dispersed into DMF (300 mL). Iodoethane (62.4 g, 0.4 mole) was added to 
the stirred suspension of polyamine, which was then stirred at 45.degree. 
C. for 2 days, then cooled and filtered. The solid was collected by 
filtration and then slurried with concentrated hydrochloric acid (200 mL) 
in water (400 mL), then filtered and washed with acetone (500 mL) water (1 
L) and ethanol (1 L). This acidification and washing was repeated until 
the washings were iodide free. The solid was then washed alternately with 
water and ethanol (1 L portions) until the washings were acid-free, then 
dried in vacuo to give the polymer product as a white solid (32 g), 
microanalysis, found: C, 46.4%; H, 10.2%; N, 7.0%; chloride, 16.8%; 
potentiometric titration showed no free HCl, but 77% amine hydrochloride, 
indicating that the product is 23% quaternised; swelling characteristics: 
water, 23; 0.15M NaCl, 11 and ethanol, 14. 
EXAMPLE 46 
Dodecamethylene cross-linked poly(N-octyl-N-butylallylamine), methyl 
quaternary derivative (38% quaternisation) 
Dodecamethylene cross-linked poly(N-octylallylamine hydrochloride (22.7 g, 
0.1 equivalents) (prepared as described in Example 24) was alkylated with 
1-iodobutane using a similar procedure to that in Example 20 but isolated 
by filtration and washing of the collected solid with ethanol. This solid 
was then slurried in a solution of sodium hydroxide (4.0 g, 0.1 mole) in 
ethanol (about 1 L) and washed thoroughly with ethanol. The solid was 
sucked dry and suspended in DMF (150 mL). Iodomethane (14.3 g, 0.1 mole) 
was added to the suspension of polyamine, which was then stirred at 
45.degree. C. for 2 days. The solid was collected by filtration and 
slurried in a solution of concentrated hydrochloric acid (200 mL) in water 
(800 mL) then washed with ethanol (1 L). This acidification and washing 
was repeated until the washings were iodide-free. The solid was then 
washed with ethanol until acid-free, then with diethyl ether and finally 
dried in vacuo. The title polymer product was obtained as a white solid 
(25 g); potentiometric titration showed no free HCl, but 62% of amine 
hydrochloride, indicating that the product is 38% quaternised; swelling 
characteristics: water, 4; 0.15M NaCl, 4; and ethanol, 5. 
EXAMPLE 47 
[This Example describes the preparation of trimethylene cross-linked 
poly(N,N-dimethylallylamine) hydrochloride required as a starting 
material.] 
Trimethylene cross-linked poly(allylamine) was prepared by a similar 
procedure to that described in Example 43 but using 0.05 mole of 
1,3-dibromopropane per equivalent of poly(allylamine) starting material 
and replacing the ethanol (60 mL) diluent by methanol (200 mL). The 
product was isolated as the hydrochloride by a similar procedure to that 
of Example 24. Potentiometric titration indicated that the equivalent 
weight of the product, as amine hydrochloride, was 156. 
A portion of this product (78.0 g, 0.5 equivalent) was swollen in a 
solution of sodium hydroxide (20 g, 0.5 mole) in water (about 400 mL). 
Formic acid (376 mL, excess) was slowly added to the stirred suspension of 
polyamine, followed by 40% w/v formaldehyde aqueous solution (364 mL, 
excess). The mixture was then refluxed, with stirring, for 2 days. The 
solid was collected by filtration, washed thoroughly with water, then 
acidified with 2N hydrochloric acid (2.4 L, excess). The solid was then 
washed acid free with water, then shrunk by washing successively in 
ethanol, acetone and ether and dried in vacuo to give the title polymer 
product as a white powder (70.5 g). Microanalysis, found: C, 41.0%; H, 
9.4%; N, 8.8%; chloride, 25.7%; potentiometric titration showed no free 
HCl and indicated that the equivalent weight of the product, as amine 
hydrochloride, was 144. 
EXAMPLE 48 
Trimethylene cross-linked poly(N,N-dimethylallylamine), octyl/methyl 
quaternary derivative (89% quaternisation) 
Trimethylene cross-linked poly(N,N-dimethylallylamine) hydrochloride (28.0 
g, 0.2 equivalent) (prepared as described in Example 47) was converted to 
the free base form by slurrying into a solution of sodium hydroxide (10 g, 
0.25 mole) in ethanol (300 mL) and water (120 mL). The solid was collected 
by filtration and washed acid-free with water, then shrunk by washing in 
ethanol, acetone and DMF. It was sucked semi-dry and slurried in DMF (200 
mL). 1-Iodooctane (14.4 g, 0.06 mole) was added to the suspension which 
was stirred at 40.degree. C. for 6 days. The solid was then collected by 
filtration, washed with water (1 L) and ethanol (1 L), then slurried in a 
solution of sodium hydroxide (14 g, 0.35 mole) in ethanol (1 L). The solid 
was then washed successively with water, ethanol, acetone and ether and 
sucked dry. It was then slurried in DMF (300 mL) and iodomethane (56.3 g, 
0.4 mole) was added. The suspension was stirred at 40.degree. C. for 2 
days, then drowned out into water (about 2 L). The solid was collected by 
filtration and washed free of iodide by repeated treatments with 
concentrated hydrochloric acid (100 mL) in ethanol (400 mL), (each 
followed by a wash with acetone). The solid was washed acid-free with 
water, then shrunk by washing successively in ethanol, acetone and diethyl 
ether, and dried in vacuo to give the title polymer product as a white 
solid (26 g); microanalysis, found: C, 48.9%; H, 10.4%; N, 7.6%; chloride, 
19.8%; potentiometric titration showed no free HCl, but 11% amine 
hydrochloride, indicating that the product is 89% quaternised; swelling 
characteristics: water, 20; 0.15M NaCl, 12; and ethanol, 10. 
EXAMPLE 49 
Trimethylene cross-linked poly(N,N-dimethylallylamine)butyl quaternary 
derivative (64% quaternisation). 
Trimethylene cross-linked poly(N,N-dimethylallylamine)hydrochloride (35.0 
g, 0.25 equivalent), prepared as described in Example 47, was converted to 
the free base form by slurrying with a solution of sodium hydroxide (12 g, 
0.3 mole) in ethanol (400 mL) and methanol (50 mL). The solid was 
collected by filtration and washed acid free with water, then shrunk by 
washing in ethanol and DMF. It was sucked semi-dry and slurried in DMF 
(300 mL). 1-Iodobutane (55.2 g, 0.3 mole) was added to the suspension 
which was stirred at 40.degree. C. for 6 days and then added to water (1 
L). The solid obtained was collected by filtration and slurried in a 
mixture of concentrated hydrochloric acid (100 mL) and ethanol (500 mL). 
The solid was filtered off and re-treated with ethanolic hydrochloric 
acid. It was then thoroughly washed with acetone and water, shrunk by 
washing with ethanol, acetone and ether, and then dried in vacuo. 
The polymer product was obtained as a white powder (34.7 g); microanalysis, 
found: C,50.4%; H,11.0%; N,7.3%; chloride 20.8%; potentiometric titration 
with 0.1N NaOH showed 14% of the chloride present as free HCl and 31% as 
amine hydrochloride, indicating that the polymer product (i.e. ignoring 
free HCl) is 64% quaternised; swelling characteristics: water, 22; 0.15M 
NaCl, 13; and ethanol, 12. 
EXAMPLE 50 
Self cross-linked poly(N-octylallylamine), dimethyl quaternary derivative 
(48% quaternisation). 
This polymer was prepared from self cross-linked poly(N-octylallylamine) 
hydrochloride using an analogous procedure to that described in Example 36 
but using less iodomethane (3 mole per 1 equivalent of polyamine) as 
quaternising agent. 
The polymer product was obtained in 62% yield; microanalysis, found: 
C,60.3%; N,11.4%; N,4.9%; chloride 15.4%; potentiometric titration showed 
no free HCl, but 52% amine hydrochloride, indicating the product is 48% 
quaternised; swelling characteristics: water or 0.15M NaCl: not wetted; 
ethanol, 8. 
EXAMPLE 51 
[This Example describes the conversion of the product of Example 2 to the 
citrate salt.] 
The product of Example 2 (3.5 g, 0.02 equivalents as the chloride salt) was 
suspended in water (350 mL). A solution of trisodium citrate (59.0 g, 0.2 
mole) in water (150 mL) was then added and the mixture was stirred 
overnight. The solid was collected by filtration and re-treated with the 
same amount of trisodium citrate solution. The resultant solid was again 
collected by filtration, thoroughly washed with water (until the washings 
were chloride free), then shrunk by washing successively with ethanol, 
acetone and then ether, and finally dried in vacuo to give trimethylene 
cross-linked poly(N,N-dimethylallylamine), butyl quaternary derivative as 
the citrate salt, obtained as a white powder (3.0 g); microanalysis, 
found: C,56.4%; H,10.2%; N,7.5%; chloride--not detectable. 
EXAMPLE 52 
Trimethylene cross-linked poly(N,N-dimethylallylamine), octyl/methyl 
quaternary derivative (91% quaternisation) 
A solution of sodium hydroxide (12.8 g, 0.32 mole) in water (4 mL) and 
methanol (88 mL) was added slowly to a solution of poly(allylamine) 
hydrochloride (category 10S; from Nitto Boseki Company Ltd; 40 g, 0.4 
equivalents) in water (20 mL) and methanol (24 mL). The mixture was 
stirred for 2 hours until homogeneous. 1,3-Dibromopropane (4.14 g, 0.02 
mole) was then added and the reaction heated to 60.degree. C. and stirred 
until it gelled (10 minutes). The mixture was allowed to stand at 
60.degree. C. for 65 hours, then worked up by a similar procedure to that 
described in Example 39. Trimethylene cross-linked poly(allylamine) was 
isolated as a colourless wet gel (816 g, A). [A sample (20 g) was 
converted to trimethylene cross-linked poly(allylamine) hydrochloride by a 
procedure similar to that described in Example 24 to give material of 
microanalysis, found: C, 32.3%; H, 9.2%; N, 11.6%; chloride, 27.4%. 
A portion of gel A (306 g) was methylated directly by a procedure similar 
to that described in Example 47, except that it was first slurried in 
water and dried by filtration. This process was repeated and the gel then 
shrunk using saturated sodium chloride solution. Liquid was removed by 
filtration and the residue was suspended in water (60 mL) stirred, and a 
solution of sodium hydroxide (6 mL, 10M) was added to adjust the pH to 11. 
After the methylation with formic acid/formaldehyde, intermediate 
trimethylene cross-linked poly(N,N-dimethylallylamine) was washed with 
water until acid free, and collected by filtration as a colourless wet 
gel, B (342 g). 
The bulk of B (331 g, ca 0.139 equivalents) was slurried in water (300 mL) 
and treated with sodium hydroxide solution (10N, 14.0 mL) for 30 minutes 
at room temperature. The solid was collected by filtration, washed with 
water (4 L), then shrunk by washing in ethanol (3.times.300 mL) and DMF 
(3.times.150 mL). It was dried by filtration to give a white solid which 
was slurried in DMF (141 mL). 1-Bromooctane (9.4 g, 0.049 mole) was then 
added to the suspension which was stirred at 45.degree. C. for 7 days. 
A portion of the cooled DMF suspension (150 mL, approximately 0.134 
equivalents) was transferred to 4 Carius tubes, diluted with DMF (150 mL 
in total), and chilled. Excess triethylamine (1.46 g, 10 mole %) and 
excess, chilled bromomethane (138 g, 1.46 mole) were added to the 
suspension. The Carius tubes were sealed using polytetrafluoroethylene 
seals, and maintained at 45.degree. C. under pressure for 7 days. The 
reaction mixture was then cooled and the solid filtered off. The solid was 
washed successively with water (2.times.500 mL), dilute hydrochloric acid 
(2N, 3.times.400 mL) and water (5.times.500 mL). The solid was finally 
suspended in water (1.5 L) and freeze-dried to give the title polymer 
(18.2 g) as a white solid. Microanalysis, (after 2 hours equilibration of 
sample, open to atmosphere) found: C, 47.5%; H, 11.1%; N, 7.5%; chloride, 
16.1%; bromide, 1.7%; H.sub.2 O 17.5%; potentiometric titration showed no 
free HCl but 9.0% amine hydrochloride, indicating that the product is 91% 
quaternised; swelling characteristics: water, 30; 0.15M NaCl, 13; and 
ethanol, 13. 
EXAMPLE 53 
[This Example describes the preparation of a trimethylene cross-linked 
poly(N,N-dimethylallylamine) hydrochloride required as a starting 
material.] 
Trimethylene cross-linked poly(allylamine) was prepared by a similar 
procedure to that described in Example 43 but using 0.05 mole of 
1,3-dibromopropane per equivalent of poly(allylamine) hydrochloride, 
(category L, molecular weight range 8500-11000, available from Nitto 
Boseki Company Ltd., of Fukushima-ken, Japan; 10 g, 0.1 equivalents) as 
starting material and replacing the ethanol diluent by methanol (6 mL). 
The product was isolated as the hydrochloride by a similar procedure to 
that in Example 24. Potentiometric titration indicated that the equivalent 
weight of the product, as amine hydrochloride, was 129. 
A portion of this product (9.72 g, 0.075 equivalent) was swollen in a 
solution of sodium hydroxide (3.52 g, 0.088 mole) in water (about 93 mL). 
Formic acid (66 mL, excess) was slowly added to the stirred suspension of 
polyamine, followed by 40% w/v formaldehyde aqueous solution (64 mL, 
excess). The mixture was then refluxed, with stirring, for 1 day. The 
solid was collected by filtration and washed thoroughly with water. A 
sample (3.5 g wet solid, ca 2%) was then acidified with a mixture of 
concentrated hydrochloric acid (2 mL) and water (30 mL). The solid 
obtained was washed acid free with water, shrunk by washing successively 
in ethanol and ether and dried in vacuo to give the title polymer product 
as a white powder (0.148 g). Microanalysis, found: C, 57.4%; H, 11.6%; N, 
12.1%; chloride, 17.8%. 
EXAMPLE 54 
Trimethylene cross-linked polT(N,N-dimethylallylamine), octyl/methyl 
quaternary derivative (93 % quaternisation) 
Trimethylene cross-linked poly(N,N-dimethylallylamine) hydrochloride, wet 
solid (168.8 g, ca 0.073 equivalent) (prepared as described in Example 53) 
was converted to the free base form by slurrying in a solution of sodium 
hydroxide (10M, 8.6 mL) in water (173 mL). The solid was collected by 
filtration and washed acid-free with water, then shrunk by washing in DMF. 
It was sucked semi-dry and slurried in DMF (87 mL). 1-Iodooctane (6.2 g, 
0.026 mole) was added to the suspension which was stirred at 45.degree. C. 
for 1 day, cooled, and poured into water (180 mL). The solid was then 
collected by filtration, washed with thoroughly with water and ethanol, 
then slurried in water (180 mL) and treated with sufficient sodium 
hydroxide solution (10M, ca 1 mL) to raise the pH to 11. The solid was 
then washed successively with water, then DMF, and sucked dry. It was then 
slurried in DMF (75 mL) and iodomethane (24.6 g, 0.173 mole) was added. 
The suspension was stirred at 45.degree. C. for 2 days, then drowned out 
into water (about 0.5 L). The solid was collected by filtration and washed 
free of iodide by repeated treatments with concentrated hydrochloric acid 
(38 mL) in ethanol (250 mL), (each followed by a wash with acetone). The 
solid was washed acid-free with water, then shrunk by washing successively 
in acetone and diethyl ether, and dried in vacuo to give the title polymer 
product as a white solid (12 g); microanalysis, found: C, 3.2%; H, 11.0%; 
N, 8.1%; chloride, 18.8%; potentiometric titration showed no free HCl but 
7% amine hydrochloride, indicating that the product is 93% quaternised; 
swelling characteristics; water, 14; 0.15M NaCl, 7; and ethanol 9. 
EXAMPLE 55 
Trimethylene cross-linked, poly(N,N-dimethylallylamine) octyl/methyl 
quaternary derivative (90% quaternisation) 
A sample of trimethylene cross-linked, poly(allylamine) was prepared by a 
similar procedure to that described in Example 52 but using 
poly(allylamine) hydrochloride (category 3S; average molecular weight 
range 7500-11000, available from Nitto Boseki Company Ltd., of 
Fukushima-ken, Japan; 10 g; 0.1 equivalents) as starting material. The 
solid obtained was isolated, washed and dried in the same way to give a 
trimethylene cross-linked, poly(allylamine) hydrochloride as a white 
powder, (9.93 g) microanalysis, found: C, 39.0%; H, 9.2%; N, 12.3%; 
chloride, 30.1% bromide 2.8%; equivalent weight based on total halide 
ion=113. 
Methylation, using formic acid and formaldehyde under reflux for 26 hours 
was carried out essentially as described in Example 52, to give 
trimethylene cross-linked poly(N,N-dimethylallylamine) hydrochloride (171 
g) as a wet colourless gel. This material (168 g, ca 0.08 equivalents), 
was basified (sodium hydroxide) and treated with 1-iodooctane (5.9 g, 
0.024 mole) and then with iodomethane (23.5, 0.17 mole), as described in 
Example 54, to give the title polymer as a white solid (12. g); 
microanalysis, Found: C, 48.0%; H, 11.1%; N, 7.5%; Cl, 17.6%; Br, nil; 
potentiometric titration showed no free HCl but 10% amine hydrochloride, 
showing that the product is 90% quaternised; swelling characteristics; 
water, 17; 0.15M NaCl 5; and ethanol, 9. 
EXAMPLE 56 
Trimethylene cross-linked, poly(N,N-dimethylallylamine), octyl/methyl 
quaternary derivative (88% quaternisation) 
A sample of trimethylene cross-linked, poly(allylamine) hydrochloride was 
prepared by a similar procedure to that described in Example 53 but using 
category H poly(allylamine) hydrochloride (average molecular weight range: 
50,000-65,000, available from Nitto Boseki Company Ltd., of Fukushima-ken, 
Japan; 10 g, 0.1 equivalents) as starting material. The solid material 
obtained was isolated, washed and dried in the same way as in Example 53 
to give the polymer product as a white powder (10.7 g); microanalysis, 
found: C, 39.5%; H, 9.5%; N, 12.8%; chloride, 31.8%; bromide, 2.5%; 
analytical equivalent weight=107.9, based on total halide. 
Methylation under reflux for 24 hours using a similar procedure to that 
described in Example 53 gave the intermediate C as a wet gel (170 g). A 
small sample of C (3.5 g) was converted to hydrochloride as described in 
Example 53 to give trimethylene cross-linked, poly(N,N-dimethylallyamine) 
hydrochloride as a white powder (0.17 g); microanalysis, found: C, 52.6%; 
H, 11.5%; N, 11.0%; chloride, 17.2%; analytical equivalent weight=206. 
The bulk sample of the intermediate C (167 g as a wet solid, ca 0.093 
equivalents) was basified (sodium hydroxide) and treated with 1-iodooctane 
(6.7 g 0.027 mole), then with iodomethane (26.5 g, 0.19 mole), as 
described in Example 54, to give the title polymer as a white solid (12.5 
g); microanalysis, found: C, 47.7%; H, 11.1%; N, 7.4%; Cl, 17.8%; Br, nil: 
potentiometric titration showed no free HCl but 12% amine hydrochloride, 
indicating that the product is 88% quaternised; swelling characteristics; 
water, 16; 0.15M NaCl, 7; and ethanol, 13. 
EXAMPLE 57 
[This Example describes the preparation of a trimethylene cross-linked 
poly(allylamine) hydrochloride required as a starting material.] 
Trimethylene cross-linked poly(allylamine) was prepared by a similar 
procedure to that described in Example 43 but using 0.05 mole of 
1,3-dibromopropane per equivalent of poly(allylamine) starting material 
and replacing the ethanol (60 mL) diluent by methanol (230 mL). The 
gelatinous mixture was dispersed in water using an high shear mixer, 
collected by filtration and then slurried in an excess of dilute aqueous 
hydrochloric acid. It was first washed acid-free with water, then with 
ethanol and dried in vacuo. The polymer product was obtained in 85% yield; 
microanalysis, found: C, 39.0%; H, 9.5%; N, 12.8%; chloride 33.1%. 
Potentiometric titration showed no free HCl, and an equivalent weight, as 
amine hydrochloride, of 110; swelling characteristics: water, 24; 0.15M 
NaCl, 18; and ethanol, 2. 
EXAMPLE 58 
Trimethylene cross-linked poly(N,N-dimethylallylamine) octyl/methyl 
quaternary derivative (91% quaternisation) 
Trimethylene cross-linked poly(allylamine) hydrochloride prepared as 
described in Example 57 (55.0 g, 0.50 equivalents) was swollen in a 
solution of sodium hydroxide (20 g, 0.5 mole) in water (about 500 mL). 
Formic acid (376 mL excess) was added slowly to the stirred suspension of 
polyamine, followed by aqueous formaldehyde solution (40% w/v, 364 mL; 
excess). The mixture was then heated under reflux with stirring for 24 
hours. The solid product was collected by filtration and thoroughly washed 
with water. It was then suspended in a solution of sodium hydroxide (20 g, 
0.5 mole) in water (about 1 L). The solid was collected by filtration, 
washed thoroughly with water to remove excess alkali, then washed with 
ethanol (200 mL) and twice with DMF (500 mL each), to give the 
intermediate poly(N,N-dimethylallylamine gel as a semi-dry paste. 
This paste was slurried in DMF (500 mL) and 1-iodooctane (36.0 g, 0.15 
mole) was added to the suspension which was stirred at 45.degree. C. for 
24 hours. The solid was collected by filtration, washed with water (2 L) 
and twice with ethanol (1 L each) and sucked dry. It was then slurried in 
a solution of sodium hydroxide (4.5 g, 0.11 mole) in water (about 1 L) to 
ensure complete conversion of amine to the free base form. The solid 
obtained was collected by filtration and washed alkali-free with water, 
then shrunk by washing three times with DMF (500 mL each) and sucked 
semi-dry. The residue slurried in DMF (500 mL) and iodomethane (142 g, 1.0 
mole) was added. The suspension was stirred at 45.degree. C. for 24 hours, 
then poured into water (about 2 L). The solid obtained was collected by 
filtration and washed free of iodide by repeated treatments with a mixture 
of concentrated hydrochloric acid (50 mL) in ethanol (1 L) and water (500 
mL), (each followed by a wash with acetone). The solid was then washed 
with water, shrunk by washing with acetone and diethyl ether, and dried in 
vacuo to give the title polymer product as a white solid (66.5 g); 
microanalysis, found: C, 53.9%; H, 11.0%; N, 7.8%; chloride, 19.1%; 
potentiometric titration showed no HCl, but 9% amine hydrochloride, 
indicating that the product is 91% quaternised; swelling characteristics: 
water, 16; 0.15M NaCl, 9; and ethanol, 9. 
EXAMPLE 59 
Representative compositions of a polymeric allylammonium derivative of the 
invention, for example such as is described in one of the previous 
Examples, suitable for administration to man for therapeutic or 
prophylactic purposes, may be obtained as follows: 
(a) Capsule 
Finely pulverised polymeric allylammonium derivative 320 mg 
Microcrystalline cellulose 80 mg 
The finely powdered materials are packed in a conventional manner into hard 
gelatine capsules. 
______________________________________ 
(b) Chewable Tablet 
Finely pulverised polymeric allylammonium derivative 
600 mg 
Microcrystalline cellulose 120 mg 
Silica 10 mg 
Sorbitol 220 mg 
Lactose 220 mg 
Magnesium stearate 12 mg 
Flavourings 5 mg 
(c) Liquid Suspension 
Finely pulverised polymeric allylammonium derivative 
1000 mg 
Sorbitol* 200 mg 
Potassium citrate 20 mg 
Benzyl alkonium chloride* 5 mg 
Flavourings 5 mg 
Deionised water to 10 mL 
______________________________________ 
*Note: an alternative conventional suspending agent or preservative may b 
substituted. 
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EMPIRICAL 
STRUCTURAL 
FORMULAE 
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##STR2## I 
##STR3## IIa 
##STR4## IIb 
##STR5## III 
##STR6## IV 
##STR7## Va 
##STR8## Vb 
##STR9## Vc 
##STR10## VI 
##STR11## VII 
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##STR12##