Compounds

Abstract: Polymers of structure: in which X is a cross-linking unit, X¹ is a comonomer unit, R¹ is hydrogen or C₁₋₄alkyl and R¹ and R² are the same or different and are each C₁₋₂alkyl or aralkyl, or R¹ to R³ together form a ring, compositions containing them and their use in therapy for the lowering of serum cholesterol levels.

Description: The present invention relates to novel anion exchange polymers, processes for their preparation, pharmaceutical compositions containing them and their use in the lowering of plasma cholesterol levels in humans. Coronary Heart Disease (CHD) is one of the most serious health problems of contemporary society. Worldwide epidemiological studies have shown that the incidence of CHD is related to a number of independent risk factors, in particular, for example, high concentrations of serum cholesterol (hypercholesterolaemia). Such adverse factors lead to atherosclerosis, and ultimately, in severe cases, intermittent claudication, cerebrovascular insufficiency, thrombosis and cardiac arrest. It is known that ion exchange polymers can be used as sequestering agents to bind bile acids and salts in the intestinal tract, forming complexes which are then excreted in the faeces. This sequestering leads to a decrease in the amount of bile acids returning to the liver via enterohepatic circulation. The synthesis of replacement bile acids from hepatic cholesterol depletes hepatic cholesterol, regulates hepatic LDL receptors and consequently reduces plasma cholesterol levels. Such sequestering polymers have been recognised as useful for the treatment of hypercholesterolaemia and it is now proven that reducing serum cholesterol with bile acid sequestrants has a beneficial effect on protecting against the occurrence of coronary heart disease. One particular agent which is currently used to lower serum cholesterol levels in humans by binding bile acids in the intestinal tract is cholestyramine. Cholestyramine is a cross-linked anion exchange polystyrene polymer bearing an ionisable trimethylammonium group bound to the polymer backbone. However, the use of this agent is associated with a number of undesirable side-effects, for example, it is unpalatable and must be taken in high doses and causes, in some cases, bloating, constipation and other gut side-effects. Furthermore, its ability to bind bile acids is inefficient with respect to the amounts of resin which it is necessary to use (up to 36 g per person per day). In addition, other polymers have been disclosed in the art as sequestering agents, in particular US 3787474 discloses the use of polymers derived from acrylic monomers of structure RCH=CHR¹A in which R is methyl or ethyl, R¹ is hydrogen or methyl and A is for example, CO₂(CH₂)₂N(R³)₂R⁴X in which R³ is methyl or ethyl, and R⁴ is hydrogen, methyl or ethyl and X is Cl⁻, Br⁻, I⁻ or CH₃SO₃-, cross-linked with methyl bisacrylamide or ethylene glycol bis methacrylate; US 4393145 discloses further polymers derived from acrylic monomers cross-linked through divinyl benzene (10 to 12%), and SE 7906129 discloses acrylic polymers cross-linked by 10-12% of a divinyl cross-linking monomer. However, despite these disclosures, no such acrylic polymers are available for human use and there remains a need for effective bile acid sequestering agents which do not have the disadvantages associated with agents currently in use. The present invention therefore provides in a first aspect, cross-linked polymers of structure (I) in which a, b and c indicate the relative molar percentages of the units present in the polymer, (a) being from 25 to 99.5 molar percent, and (b) being from 0.5 to 8 molar percent; X is a cross-linking unit; X¹ is a comonomer unit; R is hydrogen or C₁₋₄alkyl; R¹ and R² are the same or different and are each C₁₋₄alkyl, and R³ is C₁₋₂₀alkyl or C₁₋₂₀aralkyl; or R¹ is C₁₋₄alkyl and R² and R³ together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R¹ to R³ together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms; n is 1 to 20; p is a number indicating the degree of polymerisation of the polymer; and Y⁻ is a physiologically acceptable counter ion, provided that, (i) when n is 1 to 5, R¹ , R² and R³ are not all C₁₋₄alkyl; and (ii) when n is 1 to 5, R¹ , R² and R³ do not together form an unsaturated ring. Suitably, (a) is from 25 to 99.5 molar percent; preferably from 60 to 99.5 molar percent. Suitably, (b) is from 0.5 to 8 molar percent; preferably from 0.5 to 5.0 molar percent. Suitably, X is a cross-linking unit i.e. a unit which provides a random distribution of cross-links between chains of polymers. Preferred such units include, for example, divinylbenzene, alkylene glycol bis methacrylates of structure (i) in which m is 2 to 6, z is 1 to 4 and (b) comprises from 0.5 to 8 molar percent of said polymer; and trismethacrylates of structure (ii) Suitably, z is 1 to 4, preferably z is 1. Suitably, m is 2 to 6, preferably m is 2. Suitably X¹ is a comonomer unit. Preferably X¹ is styrene, an alkyl alkylate of structure (ii) or an alkylstyrene of structure (iii) in which R and c are as described for structure (I) and R⁴ is C₁₋₂₀alkyl. In such comonomers groups R is preferably methyl and R⁴ is preferably C₆₋₁₂alkyl. Suitably R¹ to R³ together with the nitrogen atom to which they are attached form an unsaturated ring optionally containing one or more further heteroatoms. Suitable examples of such rings unsaturated 5 or 6 membered rings such as imidazolyl and pyridyl. More suitably, R¹ is C₁₋₄alkyl and R² and R³ together with the nitrogen atom to which they are attached form a saturated ring optionally containing one or more further heteroatoms. Suitable examples of saturated rings include, for example, morpholino, piperidino and piperazino rings, and in addition, bicyclic rings i.e. those in which the R¹ group forms a bridge between the two nitrogen atoms of a saturated ring e.g. diazabicyclo [2.2.2] octane rings of structure Preferably, R¹ and R² are the same or different and are each C₁₋₄alkyl; more preferably R¹ and R² are the same and are each C₁₋₄alkyl, in particular methyl; and R³ is C₁₋₂₀alkyl or C₁₋₂₀aralkyl, preferably C₁₋₂₀alkyl, most preferably C₁₋₁₂alkyl, in particular C₁₂alkyl. Suitably, n is 1 to 20; preferably n is 10 to 20; most preferably n is 10 to 12. p is a number indicating the degree of polymerisation of the polymer. Owing to the three dimensional cross-linkage, precise figures cannot be given for p, but in any case will be greater than 1,000. Suitably Y⁻ is a physiologically acceptable counter ion such as a bicarbonate, carbonate, formate, acetate, sulphonate, propionate, malonate, succinate, maleate, tartrate, citrate, maleate, fumarate, ascorbate, sulphate, phosphate, halide or glucuronate; or the anion of an amino acid such as aspartic or glutamic acid. Preferably Y⁻ is a sulphate, phosphate or halide ion; more preferably a halide ion, in particular a chloride ion. It is to be noted that C₁₋₄alkyl and C₁₋₂₀alkyl groups as herein defined include both straight and branched alkyl groups. A preferred sub-class of polymers falling within the present invention is the polymers of structure (IA) in which (a), (b) and (c) indicate the relative molar percentages of the units present in the polymer, (a) being from 25 to 99.5 molar percent and (b) being from 0.5 to 8 molar percent; R is C₁₋₄ alkyl; R¹ and R² are each C₁₋₄alkyl; R³ is C₁₋₂₀alkyl or C₁₋₂₀aralkyl, or R¹ and R² are the same or different and are each C₁₋₄alkyl, and R³ is C₁₋₂₀alkyl or C₁₋₂₀aralkyl; or R¹ is C₁₋₄alkyl and R² and R³ together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R¹ to R³ together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms; n is 1 to 20; and R⁴ is C₁₋₂₀alkyl; m is 2 to 6; z is 1 to 4; Y⁻ is a physiologically acceptable counter ion; and p is a number indicating the degree of polymerisation of said polymer; provided that, (i) when n is 1 to 5, R¹ , R² and R³ are not all C₁₋₄alkyl; and (ii) when n is 1 to 5, R¹ , R² and R³ do not together form an unsaturated ring. The polymers of the present invention are also characterised by their total exchange capacity i.e. the theoretical maximum capacity of the resin if each counter ion were to be exchanged with bile acid. In this specification the total exchange capacity is defined in terms of the number of milliequivalents of counter ion per gram of dry weight of polymer. Suitable total exchange capacities are in the range of, for example where the counter ion Y⁻ is chlorine, from about 1.5 to about 5.0 meq Cl⁻ per gram of resin. Preferred within this range are polymers having a total exchange capacity of between 2 and 3 meq Cl⁻/gram of resin. It is to be noted that the term 'bile acid' when used herein shall be taken to include bile acids, bile salts and conjugates thereof. The polymers of the present invention can be prepared by processes analogous to those known in the art. The present invention therefore provides, in a further aspect, a process for preparing the polymers of structure (I) which comprises : (a) reaction of a polymer of structure (II) in which a, b, c, p, R, X, X¹ and n, are as described for structure (I), and Z is a group displaceable by an amine, with a compound of structure R¹R²R³N, in which R¹ to R³ are as described for structure (I); or (b) reaction of a polymer of structure (III) in which a, b, c, p, R, X, X¹ and n are as described for structure (I), and Z¹ is a group NR¹R³ or NR¹R² in which R¹ to R³ are as described for structure (I) with a compound of structure R⁵Z in which R⁵ is a C₁₋₄alkyl group when Z¹ is NR¹R³ or a C₁₋₂₀alkyl or C₁₋₂₀aralkyl group when Z¹ is NR¹R² and Z is a group displaceable by an amine; or (c) reaction of a polymer of structure (IV) in which a, b, c, p and R are as described for structure (I), with a compound of structure Z²(CH₂) n N ⁺R¹R²R³M⁻(V) in which n, R¹ , R² and R³ are as described for structure (I), M⁻ is a counter ion and Z² is a leaving group displaceable by a carboxylate anion. Suitable groups Z displaceable by an amine will be apparent to those skilled in the art and include for example halogen, such as bromine. Suitable leaving group Z² displaceable by a carboxylate anion will be apparent to those skilled in the art and include for example, halogen, preferably bromine, and sulphonic acids such as p-toluene sulphonic or methane sulphonic acid. Suitable counter ions M⁻ are, for example, as described herein for Y⁻. The reaction between a polymer of structure (II) and a compound of structure R¹R²R³N can be carried out in a suitable solvent at elevated temperature. Suitable solvents included for example, a C₁₋₄alkanol such as methanol, N-methylpyrrolidone, dimethylformamide, tetrahydrofuran, nitromethane or sulpholane. Preferably the reaction is carried out in methanol at a temperature of about 40° for a period of up to 24 hours or until the reaction is complete. The reaction between a polymer of structure (III) and a compound of R⁵Z can be carried out in a suitable inert solvent such as a C₁₋₄alkanol, dimethylformamide, N-methylpyrrolidone or tetrahydrofuran at elevated temperature. The reaction between a polymer of structure (IV) and a compound of structure (V) can be carried out in a suitable solvent at a temperature of between ambient and the reflux temperature of the solvent used. The intermediate polymers of structure (II) can be prepared from readily available materials by methods known to those skilled in the art. For example polymers of structure (II) in which X is a cross-link of structure (i) in which z is i and m is 2, and Z is bromine and R is methyl can be prepared by reaction of the appropriate bromo alkyl methacrylate, ethylene glycol bis methacrylate, and, optionally, for example, a C₁₋₂₀alkyl alkacrylate (if a comonomer unit X¹ is desired in the final polymer) in an aqueous suspension comprising polyvinyl alcohol in the presence of an initiator at elevated temperature. Suitable initiators will be apparent to those skilled in the art and include, for example azobisisobutyronitrile benzoyl peroxide and WAKO V601 (Trade name - MeO₂C(CH₃)₂CN=NC(CH₃)₂CO₂Me). The intermediate polymers of structure (III) can be prepared from the polymers of structure (II) by reaction with an amine of structure R¹R²NH or R¹R³NH under the same or similar conditions as indicated for the reaction of a compound of structure (II) and a compound of structure R¹R²R³N. The intermediate polymers of structure (III) can also be prepared by copolymerising a monomer of structure (VII) in which R, n, and Z¹ are as defined for structure (III) with a suitable cross-linking agent (X) and optionally a comonomer unit (X¹) in an aqueous suspension comprising polyvinyl alcohol in the presence of an initiator at elevated temperature. The intermediates of structure (IV) are available commercially or can be prepared by standard techniques. The starting monomers can be prepared by methods apparent to those skilled in the art. For example, chloro or bromo alkyl methacrylates can be prepared by reaction of the corresponding chloro- or bromoalkanol and methacrylic anhydride in the presence of 4-dimethylaminopyridine (DMAP) in a suitable solvent such as pyridine, or by reaction of the corresponding chloro or bromo alkanol with methacryloyl chloride in the presence of a base in a suitable solvent - suitable combinations of bases and solvents include, for example sodium bicarbonate in petroleum spirit as a solvent and pyridine as a base in toluene as solvent (cf. method described in Polymer (1987), 28 , 325-331, and Br.Polymer J. (1984) 16 , 39-45). The polymers of structure (I) have been found to bind bile acids both in in vitro and in in vivo models. As indicated earlier it is recognised that removal of bile acids from the intestinal tract in this way lowers serum cholesterol levels and also has a beneficial effect on protecting against atherosclerosis and its dependent clinical conditions. The present invention therefore provides in a further aspect, polymers of structure (I) for use in therapy, in particular for the lowering of serum cholesterol levels in mammals, including humans. In addition the polymers of structure (I) are expected to be of use in protecting against atherosclerosis and its sequelae, and for example, in the treatment of pruritus and diarrhoea. When used in therapy polymers of structure (I) are in general administered in a pharmaceutical composition. In a still further aspect of the present invention there is therefore provided a pharmaceutical composition comprising a polymer of structure (I) in association with a pharmaceutically acceptable carrier. The compositions of the present invention can be prepared by techniques well known to those skilled in the art of pharmacy. The polymers are preferably administered as formulations in admixture with one or more conventional pharmaceutical excipients which are physically and chemically compatible with the polymer, which are non-toxic, are without deleterious side-effects but which confer appropriate properties on the dosage form. In general, for liquid formulations, aqueous pharmaceutically acceptable carriers such as water itself or aqueous dilute ethanol, propylene glycol, polyethylene glycol or glycerol or sorbitol solutions are preferred. Such formulations can also include preservatives and flavouring and sweetening agents such as sucrose, fructose, invert sugar, cocoa, citric acid, ascorbic acid, fruit juices etc. In general, digestible oil or fat based carriers should be avoided or minimised as they contribute to the condition sought to be alleviated by use of the polymers. They are also subject to absorption by the polymers during prolonged contact, thus reducing the capacity of the polymer to absorb bile acids after administration. The polymers can also be prepared as 'concentrates', for dilution prior to administration, and as formulations suitable for direct oral administration. They can be administered orally ad libitum , on a relatively continuous basis for example by dispersing the polymer in water, drinks or food, for example in a granule presentation suitable for admixture with water or other drink to provide a palatable drinking suspension. Preferably, the polymers are administered in tablet form or in gelatin capsules containing solid particulate polymer or a non-aqueous suspension of solid polymer containing a suitable suspending agent. Suitable excipients for such formulations will be apparent to those skilled in the art and include, for example, for tablets and capsules, lactose, microcrystalline cellulose, magnesium, stearate, povidone, sodium starch, glycollate and starches; and for suspensions in capsules, polyethylene glycol, propylene glycol and colloidal silicone dioxide. If desired these dosage forms in addition optionally comprise suitable flavouring agents. Alternatively, a chewable tablet or granule presentation incorporating suitable flavouring and similar agents may be used. Preferably the polymer is administered in unit dosage form, each dosage unit containing preferably from 0.5 g to 1.5 g of polymer. The daily dosage regimen for an adult patient may be, for example, a total daily oral dose of between 1 and 10 g, preferably 1-5 g, the compound being administered 1 to 4 times a day. Suitably the compound is administered for a period of continuous therapy of one month or more sufficient to achieve the required reduction in serum cholesterol levels. In addition the polymers of the present invention can be co-administered (together or sequentially) with further active ingredients such as HMGCoA reductase inhibitors and other hypocholesterolaemic agents, and other drugs for the treatment of cardiovascular diseases. The following data and examples indicate the properties and preparation of the polymers of the present invention. Temperatures are recorded in degrees celsius. The exchange capacity of the ammonium substituted polymers was determined by elemental analysis and/or potentiometric titration of chloride ion. Figures quoted are expressed as milli equivalents of exchangeable chloride ion per gram of dry resin weight; and the percent cross-linking values given are based on the ratios of the starting monomers used in the polymerisation stage. Example 1 (a) A suspension of 11-bromoundecanol (100 g) and 4-dimethylaminopyridine (DMAP) (1 g) in methacrylic anhydride (60 ml) and pyridine (37 ml) was stirred for 48 hours at room temperature. Water (400 ml) was added and the aqueous phase brought to pH 3 using dilute hydrochloric acid. The aqueous phase was extracted with hexane (3 x 300 ml). The combined organic extracts were washed with 2M HCl (200 ml), water (200 ml), saturated sodium hydrogen carbonate solution (2 x 400 ml) and finally water (200 ml). After drying (MgSO₄), the solution was concentrated in vacuo to give a clear oil (108 g). This was subjected to column chromatography on silica gel with hexane as eluent, to give 11-bromoundecyl methacrylate as a clear oil (70.8 g; 56% yield). (b) 11-Bromoundecyl methacrylate (49.5 g), ethylene glycol bismethacrylate (0.5 g) and azobisisobutyronitrile (AIBN) (0.5 g) were mixed to give a suspension and added to a solution of poly(vinyl alcohol) (m.w. 125,000) (1.0 g) in distilled water (500 ml). The mixture was then stirred at 80° under an atmosphere of nitrogen at such a rate as to maintain the monomers in suspension. After 7 hours the stirring was stopped and the mixture poured into distilled water. The resin formed was washed by decantation with cold and hot water, filtered, and washed with acetone and ether. Drying under reduced pressure gave an approximately 1.6 molar % cross-linked 11-bromoundecyl methacrylate co-polymer containing 3.1 meq Br/g (24.7 g). (c) The above 1.6 molar % cross-linked 11-bromoundecyl methacrylate co-polymer (5.3 g) was suspended in dimethylformamide (40 ml), 33% trimethylamine in ethanol (20 ml) added, and the reaction mixture heated at 70° for 40 hours. Additional 33% trimethylamine in ethanol was added (20 ml) at 16 and 24 hours. The polymer was filtered and washed with dimethylformamide and methanol. Anion-exchange was accomplished by stirring the polymer in 2M HCl (500 ml) for 16 hours. It was then filtered and washed with 2M HCl, water, methanol and ether and finally dried under vacuum to give cross-linked 11-N,N,N-trimethylammonioundecyl methacrylate chloride ethylene glycol bismethacrylate co-polymer beads (4.93 g), (exchange capacity = 2.76 meq Cl⁻/g). Example 2 The 1.6 molar % cross-linked 11-bromoundecyl methacrylate polymer (4.05 g) prepared in Example 1(b) was suspended in dimethylformamide (50 ml), N,N-dimethyloctylamine (10 ml) added, and the mixture stirred at 60° for 16 hours. The polymer was filtered and washed with dimethylformamide and methanol. Anion-exchange was accomplished by stirring the polymer in 2M HCl (300 ml) for 16 hours. It was then filtered and washed with 2M HCl, water, methanol, and ether, and finally dried under vacuum to give cross-linked 11-N,N-dimethyl-N-octyl-ammonioundecyl methacrylate chloride co-polymer as polymer beads (4.83 g), (exchange capacity = 2.26 meq Cl⁻/g). Example 3 1.6 molar % cross-linked 11-bromoundecyl methacrylate co-polymer (4.72 g) prepared in Example 1b was suspended in pyridine (50 ml) and the mixture stirred at 80° for 24 hours. The polymer was filtered and washed with methanol. It was then stirred in 2M hydrochloric acid (500 ml) for 16 hours and refiltered. Washing was continued with 2M hydrochloric acid, water, methanol and ether and finally the product was dried under high vacuum to give cross-linked 11-(1-pyridinio)undecyl methacrylate chloride co-polymer beads (4.61 g), (exchange capacity = 2.76 meq Cl⁻/g). Examples 4-5 N,N-Dimethyldodecylamine and N,N-dimethylbenzylamine were each reacted with a 1.6 molar % cross-linked 11-bromoundecyl methacrylate co-polymer (3.1 meq Br/g) (Example 1b) in dimethylformamide at 60° to give, after work up as described in Example 2, a cross-linked N,N-Dimethyl-N-dodecylammonioundecyl methacrylate chloride co-polymer (Example 4), (exchange capacity = 1.98 meq Cl⁻/g), and a cross-linked N,N-dimethyl-N-benzylammonioundecyl methacrylate chloride co-polymer (Example 5), (exchange capacity = 2.27 meq Cl⁻/g). Examples 6-10 11-Bromoundecyl methacrylate (49 g) and ethylene glycol bismethacrylate (1 g) were copolymerised as in Example 1 to give, after washing, approximately 3.1 molar % cross-linked 11-bromoundecylmethacrylate chloride copolymer as polymer beads (29.2 g), containing 3.0 meq Br/g. Trimethylamine, as in Example 1c, N,N-dimethyloctylamine, N,N-dimethyl-dodecylamine, and N,N-dimethylbenzylamine, as in Example 2, and pyridine, as in Example 3, were each reacted with the above approximately 3.1 molar % cross-linked polymer to give the corresponding 11-substituted methacrylate chloride co-polymers with the following exchange capacities:- Example 6, trimethylammonio, 2.93 meq Cl⁻/g; Example 7, N,N-dimethyl-N-octylammonio, 2.25 meq Cl⁻; Example 8, N,N-dimethyl-N-dodecylammonio, 1.98 meq Cl⁻/g; Example 9, N,N-dimethyl-N-benzylammonio, 2.25 meq Cl⁻/g; Example 10, 1-pyridinio, 2.75 meq Cl⁻/g. Examples 11-15 11-Bromoundecyl methacrylate (49.75 g) and ethylene glycol bismethacrylate (0.25 g) were copolymerised as in Example I to give, after washing, approximately 0.8 molar % cross-linked 11-bromoundecyl methacrylate co-polymer as polymer beads (22.8 g), containing 3.1 meq Br/g. Trimethylamine, as in Example 1c, N,N-dimethyloctylamine, N,N-dimethyldodecylamine, and N,N-dimethylbenzylamine, as in Example 2, and pyridine, as in Example 3, were each reacted with the above polymer to give the corresponding 1-substituted undecylmethacrylate chloride co-polymers with the following exchange capacities:- Example 11, trimethylammonio, 2.76 meq Cl⁻/g; Example 12, N,N-dimethyl-N-octylammonio, 2.26 meq Cl⁻/g; Example 13, N,N-dimethyl-N-dodecylammonio, 1.99 meq Cl⁻/g; Example 14, N,N-dimethyl-N-benzylammonio, 2.28 meq Cl⁻/g; Example 15, 1-pyridinium, 2.78 meq Cl⁻/g. Examples 16-18 6-Chlorohexyl methacrylate (41.5 g) was prepared, as in Example 1a, from 6-chlorohexanol (50 g) and methacrylic anhydride (56.4 g). 6-Chlorohexyl methacrylate copolymer beads 4.1 meq Cl/g and containing approximately 5%, 2% and 1% w/w ( approximately 4.9, 1.9, 0.9 molar % respectively) ethylene glycol bismethacrylate as crosslinking agent were prepared by polymerising 6-chlorohexyl methacrylate, ethyl methacrylate, and ethylene glycol bismethacrylate as in Example 1b. These polymers were then sieved and either the 53-106 µm fraction for the 4.9 molar % cross-linked resin or 206-121 µm fraction for the approximately 1.9 and 0.9 molar % cross-linked resins used further. These polymers were reacted with trimethylamine as in Example 1c, to give cross-linked 6-trimethylammoniohexyl methacrylate co-polymers with the following exchange capacities: Example 16, 4.9 molar % cross-linked, 3.16 meg Cl⁻/g; Example 17, 1.9 molar % cross-linked, 2.71 meq Cl⁻/g; Example 18, 0.9 molar % cross-linked, 2.72 meq Cl⁻/g Example 19 (a) 3-Bromopropanol (200 g), methacrylic anhydride (222 g), pyridine (134 ml) were combined with dimethylaminopyridine (4 g) with cooling to 10° in an ice bath. The reaction was stirred at room temperature for 48 hours. Water (1000 ml) was added and the aqueous solution was then acidified with dilute hydrochloric acid, and extracted with hexane (3 x 500 ml). The combined organic extracts were washed with 2NHCl (500 ml), water (500 ml), saturated sodium hydrogen carbonate solution (2 x 750 ml), water (500 ml). After drying over anhydrous magnesium sulphate, the solution was concentrated in vacuo . The resulting oil was purified by distillation to give a colourless oil, bp 66-72°, 0.5Torr, (110 g). This oil was further purified by chromatography on silica gel with hexane:dichloromethane (50:50) as eluent, to give 3-bromopropylmethacrylate (94.3 g, 32%). (b) 3-Bromopropyl methacrylate (41.41 g), ethylene glycol bismethacrylate (0.5 g), ethyl methacrylate (8.09 g) and azobisisobutyronitrile (AIBN) (0.5 g) were mixed and added to a solution of poly(vinylalcohol) (m.w. 125,000) (1 g) in distilled water (500 ml). The mixture was then stirred at 80° under an atmosphere of nitrogen, at such a rate as to maintain the monomers in suspension. After 7 hours the mixture was poured into distilled water. The resin formed was washed by decantation with cold and hot water, filtered and washed with water, acetone and ether. Drying under reduced pressure gives an approximately 1% (w/w) (approximately 0.9 molar %) cross-linked 3-bromopropyl methacrylate co-polymer containing 4 meq Br/g (26.9 g, 53-106µm after sieving). (c) The above approximately 0.9 molar % cross-linked 3-bromopropyl methacrylate co-polymer (5 g) was suspended in dimethylformamide (100 ml), N,N-dimethyloctylamine (7.5 g) was added and the mixture stirred at 70° for 20 hours. The polymer was filtered and washed in a method analogous to Example 1c to give, after drying, a cross-linked 3-(N,N-dimethyl-N-octylammonio)propyl methacrylate chloride co-polymer (4.12 g) (exchange capacity 2.64 meq Cl⁻/g). Example 20 The approximately 0.9 molar % cross-linked 3-bromopropyl polymethacrylate resin (4 g) prepared in Example 19b was suspended in dimethylformamide (100 ml), N,N-dimethyldodecylamine (10.2 g) was added and the mixture stirred at 70° for 20 hours. The polymer was filtered and washed in a method analogous to Example 1c to give, after drying, a cross-linked 3-(N,N-dimethyl-N-dodecylammonio)propyl methacrylate chloride co-polymer (5.38 g) (exchange capacity 2.36 meq Cl⁻/g). Examples 21-22 3-Bromoproplylmethacrylate (49.5 g) and ethylene glycol bismethacrylate (0.5 g) were polymerised as in Example 19b to give approximately 1% (w/w) (≅ 1.05 molar %) cross-linked 3-bromopropyl methacrylate co-polymer beads containing 4.7 meq Br/g (35.9 g, 53-106µ after sieving). N,N-dimethyloctylamine, as in Example 19, N,N-dimethyldodecylamine and as in Example 20 were each reacted with the above polymer to give the corresponding cross-linked 3-substituted propylmethacrylate chloride co-polymers with the following exchange capacities: Example 21, N,N-dimethyl-N-octylammonio, 2.95 meq Cl⁻/g; Example 22, N,N-dimethyl-N-dodecylammonio, 2.57 meq Cl⁻/g; Examples 23-34 3-Bromopropylmethacrylate (41.41 g), ethylene glycol bismethacrylate (1 g), hexylmethacrylate (7.59 g) azobisisobutyronitrile (0.5 g) were polymerised as in Example 19b to give an approximately 2% w/w (≅ 2.0 molar %) cross-linked 3-bromopropyl polymethacrylate resin containing 3.97 meq Cl/g (27 g, 53-105µm after sieving). N,N-dimethyloctylamine, as in Example 19, and N,N-dimethyldodecylamine, as in Example 20, were each reacted with the above polymer to give the corresponding 3-substituted propylmethacrylate chloride co-polymers with the following exchange capacities;- Example 23, N,N-dimethyl-N-octylammonio, 2.67 meq Cl⁻/g; Example 24, N,N-dimethyl-N-docecylammonio, 2.39 meq Cl⁻/g. Examples 25-27 3-Bromopropylmethacrylate (41.41 g), ethylene glycol bismethacrylate (1 g), laurylmethacrylate (7.5 g) and azobisisobutyronitrile (0.5 g), were polymerised as in Example 19b to give an approximately 2% w/w (≅ 2.1 molar %) cross-linked 3-bromopropyl methacrylate co-polymer beads containing 3.86 meq Br/g (21.2 g, 53-106µ after sieving). Trimethylamine, as in Example 19c, N,N-dimethyloctylamine, as in Example 19, and N,N-dimethyldodecylamine, as in Example 20, were each reacted with the above polymer to give the corresponding 3-substituted propylmethacryliate chloride co-polymers with the following exchange capacities: Example 25, trimethylammonio, 3.66 meq Cl⁻/g; Example 26, N,N-dimethyl-N-octylammonio, 2.63 meq Cl⁻/g; Example 27, N,N-dimethyl-N-dodecylammonio, 2.38 meq Cl⁻/g. Examples 28-30 11-Bromoundecyl methacrylate co-polymer beads containing 3.1 meq Br/g and containing approximately 2%, 1% and 0.5% w/w (≅ approximately 2.5, 1.25 and 0.64 molar %) 1,6-hexanediol bismethacrylate as cross-linking agent were prepared by polymerising 11-bromoundecyl methacrylae and 1,6-hexanediol bismethacrylate as in Example 1b. These polymers were reacted with trimethylamine as in Example 1c to give cross-linked 11-trimethylammonioundecylmethacrylate co-polymers with the following exchange capacities: Example 28, 2.5 molar % cross-linked, 2.82 meq Cl⁻/g; Example 29, 1.25 molar % cross-linked, 2.85 meq Cl⁻/g; Example 30, 0.54 molar % cross-linked, 2.88 meq Cl⁻/g. Examples 31-33 11-Bromoundecyl methacrylate co-polymer beads containing 3.0-3.1 meq Br/g and containing 2%, 1% and 0.5% w/w (≅ 4.8, 2.4, 1.2 molar %) divinyl benzene as cross-linking agent were prepared by polymerising 11-bromoundecyl methacrylate and divinyl benzene as in Example 1b. These polymers were reacted with trimethylamine as in Example 1c to give cross-linked 11-trimethylammonioundecylmethacrylate co-polymers with the following exchange capacities: Example 31, 4.8 molar % cross-linked, 2.77 meq Cl⁻/g; Example 32, 2.4 molar % cross-linked, 2.81 meq Cl⁻/g; Example 33, 1.2 molar % cross-linked, 2.86 meq Cl⁻/g Examples 34-36 11-Bromoundecyl methacrylate co-polymer beads containing approximately 3.0-3.1 meq Br/g and containing approximately 4%, 1.6% and 0.8% w/w (≅ 3.9, 1.5, 0.8 molar %) tetraethylene glycol bismethacrylate as cross- linking agent were prepared by polymerising 11-bromoundecyl methacrylate and tetraethylene glycol bismethacrylate as in Example 1b. These polymers were reacted with trimethylamine as in Example 1c to give cross-linked 11-trimethylammonioundecyl methacrylate co-polymers with the following exchange capacities: Example 34, 3.9 molar % cross-linked, 2.75 meq Cl⁻/g; Example 35, 1.5 molar % cross-linked, 2.83 meq Cl⁻/g; Example 36, 0.8 molar % cross-linked, 2.87 meq Cl⁻/g. Examples 37-39 11-Bromoundecyl methacrylate co-polymer beads containing approximately 3.1 meq Br/g and containing 2%, 1% and 0.5% w/w (≅ 1.9, 1.0, 0.5 molar %) 2-ethyl-2-(hydroxymethyl)-1,3-propanediol trismethacrylate as cross-linking agent were prepared by polymerising 11-bromoundecyl methacrylate and 2-ethyl-2-(hydroxymethyl)-1,3-propanediol trismethacrylate as in Example 1b. These polymers were reacted with trimethylamine as in Example 1c to give cross-linked 11-trimethylammonioundecyl methacrylate co-polymers 2-ethyl-2-(hydroxymethyl)-1,3-propanediol trismethacrylate as cross-linking agent were prepared by polymerising 11-bromoundecyl methacrylate and 2-ethyl-2-(hydroxymethyl)-1,3-propanediol trismethacrylate as in Example 1b. These polymers were reacted with trimethylamine as in Example 1c to give cross-linked 11-trimethylammonioundecyl methacrylate co-polymers with the following exchange capacities: Example 37, 1.9 molar % cross-linked 2.85 meq Cl⁻/g; Example 38, 1.0 molar % cross-linked, 2.83 meq Cl⁻/g; Example 39, 0.5 molar % cross-linked, 2.91 meq Cl⁻/g. Examples 40-42 10-Bromodecanol (340 g) and methacrylic anhydride (200 g) were reacted as described in Example 1a to give 10-bromodecylmethacrylate (193 g) after chromatography in silica gel. 10-Bromodecylmethacrylate (49 g) and ethylene glycol bismethacrylate (1 g) were co-polymerised as for Example 1b to give approximately 2% w/w (≅ 3.0 molar %) cross-linked 10-bromodecyl methacrylate co-polymer beads (46.5 g). Portions of the above cross-linked polymer were separately reacted with trimethylamine, dimethyldodecylamine and pyridine as described in Examples 1, 4 and 3 to give after washing the corresponding cross-linked 10-substituted-decylmethacrylate chloride co-polymers with the following exchange capacities: Example 40, trimethylammonio, 3.1 meq Cl⁻/g; Example 41, N,N-dimethyl-N-dodecylammonio, 2.1 meq Cl⁻/g, Example 42, 1-pyridinio, 2.9 meq Cl⁻/g. Examples 43-44 10-Bromodecylmethacrylate (49.5 g) and ethylene glycol bismethacrylate (0.5 g) were co-polymerised as for Example 1b to give approximately 1% w/w (≅ 1.5 molar %) cross-linked 10-bromodecylmethacrylate co-polymer beads (42 g). Portions of the above cross-linked polymer were separately reacted with trimethylamine and N,N-dimethyldodecylamine as in Examples 1 and 4 to give, after washing, the corresponding cross-linked 10-substituted decylmethacrylate co-polymers with the following exchange capacities:- Example 43, trimethylammonio, 3.0 meq Cl⁻/g; Example 44, N,N-dimethyl-N-dodecylammonio, 2.1 meq Cl⁻/g. Examples 45-47 12-Bromododecanol (340 g) and methacrylic anhydride (200 g) were reacted as described in Example 1a to give 12-bromododecylmethacrylate (270 g) after chromatography on silica gel. 12-Bromododecylmethacrylate (46 g) and ethylene glycol bismethacrylate (0.92 g) were co-polymerised as for Example 1b to give approximately 2% w/w (≅ 3.2 molar %) cross-linked 12-bromododecylmethacrylate co-polymer beads (44.8 g). Portions of the above cross-linked polymer were separately reacted with trimethylamine, N,N-dimethyldodecylamine, and pyridine as described in Examples 1,4 and 3 to give, after washing, the corresponding cross-linked 12-substituted-dodecyl methacrylate chloride co-polymers with the following exchange capacities: Example 45, trimethylammonio, 2.9 meq Cl⁻/g; Example 46, N,N-dimethyl-N-dodecylammonio, 2.0 meq Cl⁻/g; Example 47, 1-pyridinio, 3.0 meq Cl⁻/g. Example 48 4.51 g of the 1.6 molar % cross-linked 11-bromoundecyl methacrylate co-polymer prepared in Example 1b was reacted with N-methylimidazole (10 g) in dimethylformamide (40 ml) to give, after washing as in Example 1c, the corresponding 11-(N-(N'-methylimidazolio)-undecyl methacrylate chloride co-polymer (4.12 g) (exchange capacity = 2.64 meq Cl⁻/g). Example 49 4.2 g of the 1.6 molar % cross-linked 11-bromoundecyl methacrylate co-polymer prepared in Example 1b was reacted with N-methylmorpholine (9.2 g) in dimethylformamide (40 ml) to give, after washing as in Example 1c, the corresponding 11-(N-methylmorpholinio)undecyl methacrylate chloride co-polymer (4.0 g) (exchange capacity = 2.34 meq Cl⁻/g). Example 50 4.75 g of the 1.6 molar % cross-linked 11-bromoundecyl methacrylate co-polymer prepared in Example 1b was reacted with N-methylpiperidine (8.2 g) in dimethylformamide (40 ml) to give, after washing as in Example 1c, the corresponding 11-(N-methylpiperidinio)undecyl methacrylate chloride co-polymer (4.46 g), (exchange capacity = 2.49 meq Cl⁻/g). Example 51 (a) anhydrous dimethyl sulphoxide (64 ml) was added to a solution of oxalyl chloride (52 ml) in dichloromethane (1200 ml) at -60°. After 20 minutes, 11-bromoundecanol (101.2 g) in dichloromethane (400 ml) was added to the reaction mixture. After a further 1 hour, triethylamine (280 ml) was added slowly and 10 minutes after the completion of the addition the reaction mixture was allowed to come to room temperature. The organic phase was washed with water (500 ml), 2M HCl (2 x 500 ml), and saturated sodium hydrogen carbonate solution (2 x 500 ml), dried (MgSO₄), and concentrated in vacuo . The resulting oil was distilled under reduced pressure to yield 11-bromoundecanal (b.p. 117-119°, 0.15mm Hg) (80.7 g, 81% yield). (b) A solution of (6-hydroxyhexyl)triphenylphosphonium bromide (5.0 g) in dichloromethane (20 ml) was added dropwise to a mixture of potassium tertiary-butoxide (2.8 g) in tetrahydrofuran (100 ml) at 5°. After ten minutes, 11-bromoundecanal (2.8 g) in tetrahydrofuran (20 ml) was added and the reaction stirred at 5° until TLC indicated completion of the reaction. water (20 ml) was added and the mixture then concentrated in vacuo . Water (20 ml) was added to the residue and the aqueous phase extracted with ether (2 x 50 ml). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo to give a brown oil. This was subjected to column chromatography to yield 17-bromoheptadec-6-en-1-ol (1.7 g, 45%). (c) 17-Bromoheptadec-6-en-1-ol (33.8 g) was subjected to hydrogenation in a Paar hydrogenation apparatus (3.45 bar (50 psi) initial hydrogen pressure), using ethanol as solvent and 10% palladium on charcoal as catalyst, to yield 17-bromoheptadecan-1-ol (26.1 g, 76% yield). (d) 17-Bromoheptadecyl methacrylate (14.6 g, 48% yield) was prepared, as in Example 1a, from 17-bromoheptadecan-1-ol (25 g) and methacrylic anhydride (11.1 ml). (e) A 17-bromoheptadecyl methacrylate polymer (5.3 g) containing 2.5 meq Br/g and 2 molar % ethylene glycol bismethacrylate as cross-linking agent was prepared by polymerising 17-bromoheptadecyl methacrylate (13.25 g) and ethylene glycol bismethacrylate (0.13 g) as in Example 1b. (f) The above 2 molar % cross-linked 17-bromoheptadecyl methacrylate polymer (5.2 g) was reacted with trimethylamine, as in Example 1c, to give a 17-N,N,N-trimethylammonioheptadecyl methacrylate chloride co-polymer (4.65 g) (exchange capacity = 2.35 meq Cl⁻/g). Examples 52-53 3-Bromopropyl methacrylate (Example 19a) (41.41 g), ethylene glycol bismethacrylate (0.5 g), lauryl methacrylate (8.09 g) and azobisisobutyronitrile (0.5 g), were polymerised as in Example 19b to give approximately 1% w/w (≅ 1.26 molar %) cross-linked 3-bromopropyl methacrylate co-polymer beads containing 3.74 meq Br/g (24.34 g, 53-106µ after sieving). N,N-dimethyloctylamine, as in Example 19, and N,N-dimethyldodecylamine, as in Example 20, were each reacted with the above polymer to give the corresponding 3-substituted propylmethacrylate chloride co-polymers with the following exchange capacities:- Example 52, N,N-dimethyl-N-octylammonio, 2.33 meq Cl⁻/g; Example 53, N,N-dimethyl-N-dodecylammonio, 2.14 meq Cl⁻/g. Examples 54-55 3-Bromopropyl methacrylate (41.41 g), ethylene glycol bismethacrylate (0.5 g), styrene (8.09 g) and azobisisobutyronitrile (0.5 g), were polymerised as in Example 19b to give an approximately 1% w/w (≅ 1.26 molar %) cross-linked 3-bromopropyl methacrylate co-polymer beads containing 3.97 meq Br/g (25.96 g, 53-106µ after sieving). N,N-Dimethyloctylamine, as in Example 19, and N,N-dimethyldodecylamine, as in Example 20, were each reacted with the above polymer to give the corresponding 3-substituted propylmethacrylate chloride co-polymers with the following exchange capacities: Example 54, N,N-dimethyl-N-octylammonio, 2.49 meq Cl⁻/g; Example 55, N,N-dimethyl-N-dodecylammonio, 2.21 meq Cl⁻/g. Examples 56-57 Methacrylic anhydride (236 ml) was added to a solution of 8-bromooctanol (508.9 g) in pyridine (186 ml) and hexane (1500 ml) at 10°. After 1 hour at 10°, dimethylaminopyridine (5 g) was added keeping the temperature controlled with an ice-bath. The reaction mixture was stirred for 3 days at room temperature. 2M HCl (1000 ml) was added and the hexane layer was removed. The aqueous layer was washed with hexane (500 ml). The combined organic extracts were washed with 2M HCl (2 x 500ml), water (500 ml), saturated sodium hydrogen carbonate solution (2 x 500 ml) and finally water (1000 ml). After drying (MgSO₄), the solution was concentrated in vacuo to give a clear oil (572.2 g). This was chromatographed on silica gel with hexane: dichloromethane (50:50) as eluent, to give 8-bromooctyl methacrylate (230.2 g, 37%). 8-Bromopropyl methacrylate (49.5 g), ethylene glycol bismethacrylate (0.5 g) and azobisisobutyronitrile (0.5 g), were polymerised as in Example 19b to give an approximately 1% w/w (≅ 1.48 molar %) cross-linked 3-bromooctyl methacrylate co-polymer beads containing 3.53 meq Br/g (41.66g). Trimethylamine, as in Example 1c, N,N-dimethyldodecylamine, as in Example 20, were each reacted with the above polymer to give the corresponding 8-substituted octylmethacrylate chloride co-polymers with the following exchange capacities. Example 56, trimethylammonio, 3.15 meq Cl⁻/g; Example 57, N,N-dimethyl-N-dodecylammonio, 2.02 meq Cl⁻/g. Example 58 6-Chlorohexyl methacrylate ethylene glycol bismethacrylate co-polymer (4.1 meq Cl/g, approximately 1.9 molar % cross-linking) (c.f. Example 17) (14.1 g) was reacted with sodium bromide (6 g) and ethyl bromide (63.2 g) in N-methylpyrrolidone (200 ml) at 65° for 6 days. The slurry was then sieved and the fraction <53µM discarded. The remaining polymer was washed with water, methanol, acetone and diethylether and dried under vacuum for 16 hours to give 6-bromohexyl methacrylate ethylene glycol bismethacrylate co-polymer (14.97 g, 3.47 meq Br/g, no Cl detected). The above polymer (4 g) was reacted with N,N-dimethyloctylamine (7.6 g) in dimethylformamide (40 ml) at 70° for 16 hours. The mixture was then cooled and sieved and the fraction <53µM discarded. The remaining polymer was washed with methanol, aqueous 2N hydrochloric acid, water, methanol and diethyl ether, dried under vacuum to give the corresponding 6-N,N-dimethyl-N-octylammoniohexyl methacrylate chloride ethylene glycol bismethacrylate co-polymer as off-white polymer beads (4.72 g, 2.42 meq Cl⁻/g). Example 59 The 6-bromohexyl methacrylate co-polymer prepared in Example 58 (3.66 g) was reacted with N,N-dimethyldodecylamine (7.75 g) in dimethylformamide (40 ml) as for Example 58 and after similar work-up gave approximately 1.9 molar % cross-linked N,N-dimethyl-N-dodecylammonio hexyl methacrylate chloride ethylene glycol bismethacrylate co-polymer as off-white polymer beads (5.01 g, 2.1 meq Cl⁻/g). Example 60 6-Chlorohexyl methacrylate ethylene glycol bismethacrylate co-polymer (4.1 meq Cl/g, approximately 0.9 molar % cross-linking) (c.f. Example 17) (7.30 g) was reacted with sodium bromide (3.1 g) and ethyl bromide (32.7 g) in N-methylpyrrolidone (200 ml) at 65° for 6 days. The slurry was then sieved and the fraction <53µM discarded. The remaining polymer was washed with water, methanol, acetone and diethylether and dried under vacuum for 16 hours to give 6-bromohexyl methacrylate ethylene glycol bismethacrylate co-polymer (6.82 g, 3.4 meq Br/g, no Cl detected). The above polymer (3.4 g) was reacted with N,N-dimethyloctylamine (7.6 g) in dimethylformamide (40 ml) at 70° for 16 hours. The mixture was then cooled and sieved and the fraction <53µM discarded. The remaining polymer was washed with methanol, aqueous 2N hydrochloric acid, water, methanol and diethyl ether, dried under vacuum to give the corresponding 6-N,N-dimethyl-N-octylammoniohexyl methacrylate chloride ethylene glycol bismethacrylate co-polymer as off-white polymer beads (3.47 g, 2.45 meq Cl⁻/g). Example 61 The 6-bromohexyl methacrylate co-polymer prepared in Example 60 (3.28 g) was reacted with N,N-dimethyldodecylamine (7.75 g) in dimethylformamide (40 ml) as for Example 58 and after similar work-up gave approximately 0.9 molar % cross-linked N,N-dimethyl-N-dodecylammonio hexyl methacrylate chloride ethylene glycol bismethacrylate co-polymer as off-white polymer beads (4.37 g, 2.14 meq Cl⁻/g). Example 62 10-Bromodecyl methacrylate (47.75 g) and ethylene glycol bismethacrylate (0.25 g) were polymerised as described in Example 19b to give a co-polymer (41.5 g) containing 3.2 meq Br/g and approximately 0.5% w/w (0.8 molar %) cross-linked. This polymer (7.78 g) was treated with 33% alcoholic trimethylamine (50 ml) in DMF (170 ml) as described for Example 1c to give, after similar work up, approximately 0.8 molar % cross-linked 10-trimethylammonioundecyl methacrylate chloride ethylene glycol bismethacrylate co-polymer as off-white beads (6.42 g, 3.1 meq Cl⁻/g). Example 63 11-Bromoundecyl methacrylate tetraethylene glycol bismethacrylate co-polymer (3.1 meq Br/g, approximately 1.5 molar % cross-linking, c.f. Example 34) was reacted with N,N-dimethyloctylamine as in Example 2 to give 11-(N,N-dimethyl-N-octylammonioundecyl) methacrylate chloride tetraethylene glycol bismethacrylate co-polymer as off-white beads (2.25 meq Cl⁻/g). Example 64 11-Bromoundecyl methacrylate tetraethylene glycol bismethacrylate co-polymer (3.1 meq Br/g, approximately 0.8 molar % cross-linked c.f. Example 35) was reacted with N,N-dimethyloctylamine as in Example 2 to give 11-(N,N-dimethyl-N-octylammonioundecyl) methacrylate chloride tetraethylene glycol bismethacrylate co-polymer as off-white beads (2.25 meq Cl⁻/g). Example 65 12-Bromododecyl methacrylate (49.5 g) and ethylene glycol bismethacrylate (0.5 g) were co-polymerised as for Example 1b to give approximately 1% w/w (≅ 1.6 molar %) cross-linked 12-bromododecyl methacrylate co-polymer beads (38.8 g). This polymer was reacted with trimethylamine as described in Example 1 to give 12-trimethylammoniododecyl methacrylate chloride ethylene glycol bismethacrylate co-polymer beads (2.78 meq Cl⁻/g, approximately 1.6 molar % cross-linked). Example 66 12-Bromododecyl methacrylate (49.75 g) and ethylene glycol bismethacrylate (0.25 g) were co-polymerised as for Example 1b to give approximately 0.5% w/w (≅ 0.8 molar %) cross-linked 12-bromododecyl methacrylate co-polymer beads (20 g). This polymer was reacted with trimethylamine as described in Example 1 to give 12-trimethylammoniododecyl methacrylate chloride ethylene glycol bismethacrylate co-polymer beads (2.74 meq Cl⁻/g, approximately 0.8 molar % cross-linked). Example A A chewable tablet composition can be prepared from the following : mg/tablet Compound of Example 6: 1250 Silicon dioxide 15 Microcrystalline cellulose 280 Sorbitol 445 Lactose 450 Sweetener 5 Peppermint 30 Magnesium Stearate 25 2500 mg Example B A food additive composition, for example, a sachet for reconstitution or mixing with food, is prepared by incorporating into a powder formulation compound of Example 6 (250 mg), sodium carboxymethylcellulose (50 mg), sucrose (2400 mg) and flavours (50 mg). DATA In vitro Dissociation assay The following assay provides a measure of affinity of the polymers of the invention for the bile acid, glycocholrate (GC) based on the amount of GC bound at a subsaturating concentration of 5mM (t=0), and an estimate of the rate at which this bile acid dissociates into a large volume of buffer. The results are obtained as initial amounts of GC bound (t=0) and amounts remaining bound after 2 minutes in buffer (t=2min); from these figures the % dissociation i.e. the proportion of bound GC dissociated from the polymer after 2 minutes can be obtained. The lower the % dissociation the more efficient the polymer can be expected to be in extracting bile acids in vivo. Method Test compound (150 mg) was equilibrated with 5mM sodium glycocholate (30 ml) in Krebs' buffer. The compound was separated by centrifugation and the total bound determined by subtraction of the amount in the supernatant from the total bile acid used. Dissociation was measured by resuspending the compound in Krebs' buffer, shaking and sampling the mixture through a filter at several time points up to 20 minutes. Radioactivity and hence bile acid dissociated was determined in the filtrate. Results The following % dissociation figures were obtained : Examples % Dissociation (range) 1 to 15, 17, 20 to 24 27 to 51, 58 to 65 4 to 15 16, 18, 19, 25, 26 and 54 to 58 16 to 36 As the results demonstrate, the claimed series of compounds represent a series of polymers having a high capacity for binding bile acids at equilibrium. This capacity is particularly apparent when the compounds of the invention are compared with related acrylic polymers in which, for example n is 1 to 5 and R¹ to R³ are all C₁₋₄alkyl (of: US 3,787,474). To illustrate this, two 3-trimethylamminiopropyl methacrylate chloride copolymer (examples A and B prepared according to the procedures analogous to those hereinbefore described) were tested in the same assay and compared to the closest analogues of the claimed invention. The results are summarised in Table 1, in which EGBMA is ethylene glycol bis-methacrylate, and EMA is ethyl methacrylate. Test Compound Example No. %Cross-link X X¹ n NR¹R²R³ %Diss'n A 1.6 EGBMA - 3 NMe₃ 100 2 1.6 EGBMA - 3 NMe₂Octyl 12 1 1.6 EGBMA - 11 NMe₃ 5 22 1.6 EGBMA - 3 NMe₂Dodecyl 8 43 1.6 EGBMA - 10 NMe₃ 7 B 1.6 EGBMA EMA 3 NMe₃ 62 18 1.6 EGBMA EMA 6 NMe₃ 32 19 1.6 EGBMA EMA 3 NMe₂Octyl 23 20 1.6 EGBMA EMA 3 NMe₂Dodecyl 10 60 1.6 EGBMA EMA 6 NMe₂Octyl 14 61 1.6 EGBMA EMA 6 NMe₂Dodecyl 5

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A polymer of structure (I) in which a, b and c indicate the relative molar percentages of the units present in the polymer, (a) being from 25 to 99.5 molar percent, and (b) being from 0.5 to 8 molar percent; X is a cross-linking unit; X¹ is a comonomer unit; R is hydrogen or C₁₋₄alkyl; R¹ and R² are the same or different and are each C₁₋₄alkyl, and R³ is C₁₋₂₀alkyl or C₁₋₂₀aralkyl; or R¹ is C₁₋₄alkyl and R² and R³ together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R¹ to R³ together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms; n is 1 to 20; p is a number indicating the degree of polymerisation of the polymer; and Y⁻ is a physiologically acceptable counter ion, provided that (i) when n is 1 to 5, R¹ , R² and R³ are not all C₁₋₄alkyl, and (ii) when n is 1 to 5, R¹ , R² and R³ do not together form an unsaturated ring. A polymer as claimed in claim 1 of structure (IA) in which (a), (b) and (c) indicate the relative molar percentages of the units present in the polymer, (a) being from 25 to 99.5 molar percent and (b) being from 0.5 to 8 molar percent; R is C₁₋₄ alkyl; R¹ and R² are the same or different and are each C₁₋₄alkyl, and R³ is C₁₋₂₀alkyl or C₁₋₂₀aralkyl; or R¹ is C₁₋₄alkyl and R² and R³ together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R¹ to R³ together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms; n is 1 to 20; and R⁴ is C₁₋₂₀alkyl; m is 2 to 6; z is 1 to 4; Y⁻ is a physiologically acceptable counter ion; and p is a number indicating the degree of polymerisation of said polymer; provided that, (i) when n is 1 to 5, R¹ , R² and R³ are not all C₁₋₄alkyl, (ii) when n is 1 to 5, R¹ , R² and R³ do not together form an unsaturated ring. A polymer as claimed in claim 2 in which z is 1 and m is 2. A polymer as claimed in claim 3 in which n is 10 to 12. A polymer as claimed in claim 4 in which R¹ to R³ are all C₁₋₄alkyl. A polymer as claimed in claim 5 which is 11-N,N,N-trimethylammonioundecyl methacrylate chloride ethylene glycol bismethacrylate co-polymer, or 12-N,N,N-trimethylammoniododecyl methacrylate chloride ethylene glycol bismethacrylate co-polymer. A polymer of structure (I) as claimed in any one of claims 1 to 6 for use as in therapy. A polymer of structure (I) as claimed in any one of claims 1 to 6 for use in the lowering of serum cholesterol levels. A pharmaceutical composition comprising a polymer of structure (I) as claimed in any one of claims 1 to 6, in association with a pharmaceutically acceptable carrier. A process for preparing a polymer as claimed in claim 1 in which comprises: (a) reaction of a polymer of structure (II) in which a, b, c, p, R, X, X¹ and n, are as described for structure (I), and Z is a group displaceable by an amine, with a compound of structure R¹R²R³N, in which R¹ to R³ are as described for structure (I); or (b) reaction of a polymer of structure (III) in which a, b, c, p, R, X, X¹ and n are as described for structure (I), and Z¹ is a group NR¹R³ or NR¹R² in which R¹ to R³ are as described for structure (I) with a compound of structure R⁵Z in which R⁵ is a C₁₋₄alkyl group when Z¹ is NR¹R³ or a C₁₋₂₀alkyl or C₁₋₂₀aralkyl group when Z¹ is NR¹R² and Z is a group displaceable by an amine; or (c) reaction of a polymer of structure (IV) in which a, b, c, p and R are as described for structure (I), with a compound of structure Z²(CH₂) n N ⁺R¹R²R³M⁻(V) in which n, R¹ , R² and R³ are as described for structure (I), M⁻ is a counter ion and Z² is a leaving group displaceable by a carboxylate anion. Claims for the following Contracting States : GR, ES A process for preparing a polymer of structure (I) in which a, b and c indicate the relative molar percentages of the units present in the polymer, (a) being from 25 to 99.5 molar percent, and (b) being from 0.5 to 8 molar percent; X is a cross-linking unit; X¹ is a comonomer unit; R is hydrogen or C₁₋₄alkyl; R¹ and R² are the same or different and are each C₁₋₄alkyl, and R³ is C₁₋₂₀alkyl or C₁₋₂₀aralkyl; or R¹ is C₁₋₄alkyl and R² and R³ together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R¹ to R³ together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms; n is 1 to 20; p is a number indicating the degree of polymerisation of the polymer; and Y⁻ is a physiologically acceptable counter ion, provided that (i) when n is 1 to 5, R¹ , R² and R³ are not all C₁₋₄alkyl, and (ii) when n is 1 to 5, R¹ , R² and R³ do not together form an unsaturated ring. which comprises (a) reaction of a polymer of structure (II) in which a, b, c, p, R, X, X¹ and n, are as described for structure (I), and Z is a group displaceable by an amine, with a compound of structure R¹R²R³N, in which R¹ to R³ are as described for structure (I); or (b) reaction of a polymer of structure (III) in which a, b, c, p, R, X, X¹ and n are as described for structure (I), and Z¹ is a group NR¹R³ or NR¹R² in which R¹ to R³ are as described for structure (I) with a compound of structure R⁵Z in which R⁵ is a C₁₋₄alkyl group when Z¹ is NR¹R³ or a C₁₋₂₀alkyl or C₁₋₂₀aralkyl group when Z¹ is NR¹R² and Z is a group displaceable by an amine; or (c) reaction of a polymer of structure (IV) in which a, b, c, p and R are as described for structure (I), with a compound of structure Z²(CH₂) n N ⁺R¹R²R³M⁻(V) in which n, R¹ , R² and R³ are as described for structure (I), M⁻ is a counter ion and Z² is a leaving group displaceable by a carboxylate anion. A process as claimed in claim 1(a) when carried out in a C₁₋₄alkanol as a solvent. A process as claimed in claim 2 in which the solvent is methanol. A process as claimed in claim 3 in which the reaction is carried out at a temperature of about 40°. A process as claimed in any one of claims 1 to 4 when used to prepare a polymer of structure (IA) in which (a), (b) and (c) indicate the relative molar percentages of the units present in the polymer, (a) being from 25 to 99.5 molar percent and (b) being from 0.5 to 8 molar percent; R is C₁₋₄ alkyl; R¹ and R² are the same or different and are each C₁₋₄alkyl, and R³ is C₁₋₂₀alkyl or C₁₋₂₀aralkyl; or R¹ is C₁₋₄alkyl and R² and R³ together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R¹ to R³ together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms; n is 1 to 20; and R⁴ is C₁₋₂₀alkyl; m is 2 to 6; z is 1 to 4; Y⁻ is a physiologically acceptable counter ion; and p is a number indicating the degree of polymerisation of said polymer; provided that, (i) when n is 1 to 5, R¹ , R² and R³ are not all C₁₋₄alkyl, (ii) when n is 1 to 5, R¹ , R² and R³ do not together form an unsaturated ring. A process according to claim 5 in which the polymer of structure (IA) is 11-N,N,N-trimethylammonioundeconyl methacrylate chloride ethylene glycol bismethacrylate copolymer or 12-N,N,N-trimethylammoniododecyl methacrylate chloride ethylene glycol bismethacrylate co-polymer. A process for preparing a pharmaceutical composition which comprises bringing into association a polymer of structure (I) as described in claim 1 and a pharmaceutically acceptable carrier. A process as claimed in claim 7 in which the polymer is of structure (IA) as described in claim 5.

Inventors: ALSTON DAVID, HICKEY DEIRDRE MARY BERNADETTE, JAXA-CHAMIEC ALBERT ANDRZEJ, ALSTON, DAVID, HICKEY, DEIRDRE MARY BERNADETTE, JAXA-CHAMIEC, ALBERT ANDRZEJ
Applicants: SMITH KLINE FRENCH LAB, SMITH KLINE & FRENCH LABORATORIES LIMITED
Application year: 1989
Main classification: C08F8
IPC codes: C08F220, B01J41, C08F20, C08F8, A61K31, A61P3