NO741963L - - Google Patents

Description

New ionic polymers

The present invention relates to new polymers and methods for their production. More particularly, the invention relates to polymers derived from oxazolines and dihydro-oxazines which have a linear chain free of both branching and cross-linking, and comprising either tertiary or quaternary nitrogen atoms bonded to each other via ethylene or trimethylene groups.

These polymers are advantageously used as antimicrobial agents, flocculants, electrically conductive agents in paper dyes, antistatic agents, chelating agents and bile acid binding agents, as well as in similar applications where their high charge to weight ratio, and the availability of their nitrogen can be advantageously used.

They are particularly useful as non-absorbable gastrointestinal bile acid binding agents because such binding is known to reduce the level of blood serum cholesterol. All available information indicates that the occurrence of higher than normal blood serum cholesterol levels in humans (especially in so-called type II Fredericksom patients) is associated with atherosclerosis and other signs of hypercholesteremic disease. Atherosclerosis makes itself known by the effects of occlusion of the circulation, and causes coronary, cerebro-vascular and some forms of peripheral vascular diseases, and is the most frequent cause of death in many countries.

In an attempt to reduce the incidence of atherosclerosis, high blood serum cholesterol levels are the target of various regulatory measures, including restricted and special diets, inhibition of cholesterol synthesis, accelerated catabolism, prevention of gastrointestinal absorption, as well as by binding of bile acids in the gastrointestinal tract. The latter method is strongly preferred as it requires neither surgical intervention nor sudden and serious changes in the patients' dietary habits or lifestyle.

However, the precise mechanism by which gastrointestinal bile acid sequestration achieves lowering of the blood serum cholesterol level is unknown. It is believed that feedback mechanisms affect cholesterol oxidation responses and deplete serum cholesterol in an attempt to restore bile acid levels. Regardless of the uncertainty regarding the mechanism, the method is well accepted.<*>What is missing is a convenient, effective, non-toxic and easily tolerated binder.

Until now, a number of bile acid binding agents have been used. These include iron salts that form insoluble precipitates with bile acids, organic bases that act in a similar way, and polymers with salt-forming ability. However, absorbable traps represent acute and chronic poisoning hazards. The use of non-absorbable polymers to avoid such toxic problems has not provided a suitable alternative, because the average effective daily dose for adults of such polymers used so far is up to 40 g. The physical volume of such a dose, especially of a water -insoluble cross-linked resin, can cause partial blockage of the gastrointestinal tract and gives an unpleasant, heavy feeling. Furthermore, an unpleasant smell or taste from such a large dose is difficult to mask.

Preparations of the gel type which have less cross-linking and are branched, as the term is used here, swell markedly upon water absorption, and although they are relatively free. for rubbing irritation, they cause. often press.ubeh.ag.

Water-soluble polymers that have hitherto been proposed for use as bile acid-binding agents cause very high viscosities in the solution, and have marked astringent effects in the oral cavity. Furthermore, they have a large volume for consumption as they absorb as much as eri' equivalent weight of water in dry form. More seriously, they can be broken down in the gastrointestinal tract.

Consequently, there has been only limited benefit in treatment with this method, although the incidence of diseases linked to hyper-cholestermia is very high and continues to rise alarmingly.

Several explanations have been put forward for the inability of the resins which have hitherto been proposed to be used in hypercholesterolemic agents to balance bile acid absorption with the ability to bind chloride. One view is that smaller inorganic anions can easily reach the binding sites. Therefore, in order to form a more effective resin, a greater separation of the binding sites for bulky acids should be provided. Another view is that resins must be more lipid-like in order to penetrate in vivo the cell formations that contain fat-like bile acids, which leads to the suggestion that reduced water solubility of resins was desirable.

Unfortunately, these views have led to little improvement when transferred to polymer construction for the treatment of hypercholesterolemia.

It has now been shown that the new polymers described here are unusually effective in binding or forming complexes with bile ducts in the gastrointestinal tract, and in lowering blood serum levels of cholesterol.

By the expression "salt-forming nitrogen" is meant a nitrogen atom, e.g. an imino group or a substituted imino group which is sufficiently basic that it is either present in the form of a quaternary salt or an acid addition salt or can form one with acids.

The term "linear polymer main chain" is used to describe a polymer with only acyclic groups, ie methylene or trimethylene or trimethylene groups, attached to the nitrogen atoms in a single continuous chain.

The term "unbranched" is used to denote a poly-radr which has no repeating monomer units protruding from the polymeric backbone, and the term "cross-linked" is commonly used to denote a connection between two backbones.

That the polymers according to the invention are linear and unbranched is of the greatest importance for the understanding of the advances in the present invention. While thus some publications, e.g. US patent 3 30.8 020 relates to monomer units similar to the monomer units of the present invention, it must be remembered that these previously known polymers, due to the materials and methods used to prepare them, are highly branched. Furthermore, as far as is known, Gibbs et al, Journal of American Chemical Society, 57_ (1137

(1935) and Noguchi et al, Macromolecules, 5_, 261 (1972) are correct when they claim that attempts to polymerize dimethylaminoethylene halides give only cyclic dimers, despite the statements in German patents 1,131,694 and 1,126,396.

The polymers according to the invention have the general formula:

where -and F^/which are the same or different, are hydrogen; lower alkyl; monohydroxy substituted C 1 to C 4 alkyl, polyhydroxy substituted C 3 to C 8 alkyl or polyhydroxy substituted C 1 to C 8 cycloalkyl; C 3 to C 1 cycloalkyl; C3 to C7 cycloalkyl-substituted lower alkyl; lower alkyl-substituted C3 to C7 cycloalkyl; ammonium lower alkyl; lower alkylammonia lower alkyl; dilave-alkylammoniolave-alkyl; trilower alkylammonia lower alkyl; carboxyl lower alkyl; carbolaverealkylloweralkyl; C3 to C1alkenyl; C31 - C-y alkynyl; aralkyl, e.g. 2-(1-naphthyl)-ethyl, benzyl; carbamyl lower alkyl; fluorine lower alkyl, e.g. c -trifluorolower alkyl; cyano lower alkyl; guanidinolower alkyl; carbamidinolaverealkyl; N-lower alkylcarbamidon lower alkyl; lower aralkyl lower alkyl; lower alkylthio lower alkyl; furanosyl; pyranosyl, e.g. ot-B-glucopyranosyl; or lower alkanoyl lower alkyl.

R 3 and , which are the same or different, are lower alkyl; monohydroxy substituted C 1 to C 8 alkyl, polyhydroxy substituted C 3 to C 8 alkyl or polyhydroxy substituted C 1 to C 8 cycloalkyl; C 1 to C 7 cycloalkyl; C3 to C-, cycloalkyl-substituted lower alkyl; lower alkyl-substituted C 1 to C-, cycloalkyl; ammoniolaverealkyl;" loweralkylammoniolaverealkyl; dilaverealkylammoniolaverealkyl> trilaverealkylammoniolaverealkyl; carboxylaverealkyl; carbolaverealoxylaverealkyl; C3 to C-, alkenyl; C3 to C- j alkynyl; aralkyl, e.g. 2-(1-naphthyl). -ethyl, benzyl; carbamyllaverealkyl; fluorolaverealkyl, f .eg w-trifluorolower alkyl; cyano lower alkyl; guanidino lower alkyl; carbamidon lower alkyl; N-lower alkyl-carbamidin lower alkyl; lower alkoxy lower alkyl;.' lower alkylthiolower alkyl; furanosyl; pyranosyl, eg α-j}-gluco^pyranosyl; or lower alkanoyl lower alkyl.

n is an integer so that the weight average molecular weight is from 300 to 50000j

m is 0 or•1;

Z is a monovalent or polyvalent counteranion;

Q is ethylene or trimethylene, and

the symbol denotes an entry to several of the groups

where Q, Z, m, R-^, R2 / Rj-°9R 4 are as indicated above. T-^ and T2 are end groups on the polymer and are

or a dihydro-1,3-oxazolinium or an A-oxazolinium complex with an anion of the initiator where £3/Z, m and Q are as above, R5 is selected from the same group as R-^ and , but may be the same or different from one or both of R 1 and R 3 , and R is a fragment derived from a solvent in which the ring opening was performed, e.g. hydrogen if an aqueous treatment was used, or an alkyl if an alcoholic treatment was used.

The precise nature of the identity of T is really immaterial to the invention, or the utility of the polymers described hereafter.

The term "lower" is used here to denote from 1 to 4 carbon atoms, and can, like the above-mentioned alkyl groups, be a straight chain.

If in the above m is 1, Q is trimethylene and R 1 , R 2 , R 3 and R 1 are lower alkyl, the compounds thus described are known. Nevertheless, the methods indicated here for preparing these compounds are new.

In a preferred embodiment, the polymer has the structure indicated by the following formula: where denotes a bond to one or more groups

Z, T-^, Qim and n are as indicated above.

In another preferred embodiment, the polymer has the structure indicated by the following formula: where denotes the structure indicated by one or more groups:

Z ,, T2.'<T>2'®'m°9n is sora indicated above.

In this description, Z denotes an anion which counteracts the charge on the quaternary or protonated imino group, and can thus be an ethene-valent anion. However, it will be understood that Z can also include multivalent anions where an anion can counteract the charge on more than one charged imino group. Z can thus include anions from inorganic acids as well as from organic acids such as e.g. halide, e.g. chloride, bromide or iodide; sulfate; bisulfate; phosphate; acetate; ascorbate; citrate; hydroxycitrate; carbonate; bicarbD-nate; nicotinate; glycinate; taurinate; salicylate; and other anions derived from physiologically non-toxic acids, particularly salts of physiologically active acids such as those derived from clofibrate and halofenate,

i.e. 2-(p-chlorophenoxy)-2-methylpropionic acid and 3-trifluoromethylphenoxy-(4-chlorophenyl)-acetic acid. When such anions of physiologically active compounds are used to neutralize quaternary or protonated imino groups, it is obvious that only a part of the charged dmino groups can be neutralized in this way. The amount of anion from the physiologically active compound • is adjusted in such a ratio that the amount administered with the polymer dose can fall within the desired range for the physiologically active compound.

The polymers according to the invention are obtained by a series of steps, the first of which is the polymerization of an A 2-oxazoline with the formula: a 5,6-dihydro-4H-1,3-oxazine with the formula:

t

where R' is hydrogen, lower alkyl, phenyl, naphthyl or naphthylmethyl.

Preferably R' is hydrogen.

Stage T - Polymer isation.

The polymerization, ay. 2-R'.-A. The 2-oxazolines are known and described in. Polymer Journal, 3y 35 (19.72). However, it has been shown that a more reliable polymerization is obtained by using trifluoromethylsulfonic acid instead of the initiators indicated in the literature.

In general, from 0.005 to 0.1 mol of trifluoromethylsulfonic acid is used for each mole of a 2-R<1->A<2>~oxazoline, with 0.01 mol of trifluoromethylsulfonic acid per mol 2-R'-A 2-oxazoline is preferred.

The polymerization of 2-R'-5,6-dihydro-4H-1,3-oxazine is also known, and discussed in Macromolecules, 6_, 495 (1973). The preferred initiator among the known initiators is methyl iodide.

In general, the polymerization of the 2-R'-A 2-exa-zolines and 2-R'-5,6-dihydro-4H-1,4-oxazines is carried out in a closed system in an inert solvent and under an inert atmosphere which nitrogen, at a pressure of 1 - 100 atm and heating to from 30° C to 120° C for 1-12 hours. By inert solvent is meant here and elsewhere in the description, a solvent which is not reactive under these conditions, either with reactants, products or in itself, dimethylformamide being the preferred solvent here.

When the reaction is deemed to be complete, as determined by the disappearance of the -C=N double bond, the polymerization reaction mixture, which now comprises the polymer, becomes: where R<1>, Q and n are as above, and T, is

where Y is an anion from the initiator, A is hydrogen or an initiator fragment such as methyl from methyl iodide, and Q and R as indicated above, treated with an anhydrous solvent, preferably an alcohol or ether such as methanol or ethyl ether. After filtering and washing

ing with anhydrous solvent, the polymer is collected and dried.

After isolation, the polymer is then subjected to one of three alternative, step two: hydrolysis, direct reduction, or reductive methylation.

Step 2A Hydrolysis

The hydrolysis which cleaves the acyl group is carried out by reacting the polymer VI with an aqueous acid such as aqueous mineral acid, e.g. hydrochloric acid, or a base such as alkali hydroxide which gives the polymer:

where A, m, Q, Z, R and n are as above, and Z is preferably a halide.

The alkaline hydrolysis is carried out by mixing the polymer with an aqueous solution of saturated to 0.1N base, alkaline hydroxide, and preferably sodium hydroxide. The acid hydrolysis is carried out in a 1 - 2 N aqueous mineral acid, e.g. hydrochloric or sulfuric acid.

The hydrolysis is carried out with stirring and heating for at least

3 to 30 hours. Preferably, in order to obtain substantially complete hydrolysis and: a slight sacrifice in molecular weight, the hydrolysis may be carried out in a closed vessel at a temperature of from 40° C. to 180° C. The amount of aqueous hydrolyzing solution is not critical, provided that the stirring is good and that at least twice the theoretical amount of alkali or acid is used to effect the hydrolysis.

From the base hydrolysis, the polymer VII is obtained where m is 0, and the acid hydrolysis or subsequent acidification of the base hydrolysed polymer gives the polymer VII where m is 1.

Step 2B - direct reduction

Polymer VI is reduced directly to polymer VIII by reduction of the acyl group.

where A, Z, Q, R<1>, R , Z, m and n are as indicated above.

Preferably, the polymer is dissolved in an inert solvent and mixed slowly with at least one molar equivalent of a chemical reducing agent such as diborane, which is also dissolved in an inert solvent. The preferred solvents are tetrahydrofuran and mixtures thereof with ethylene glycol dimethyl ether. After the addition, the reaction mixture is boiled under reflux for 1 - 12 hours, cooled and acidified. Other reducing agents which can be used in place of the diborane include aluminum hydride, lithium aluminum hydride and lithium trimethoxy aluminum hydride.

Alternatively, the amide groups of polymer VI are transferred by alkylation to iminoesters with triethyloxonium-tetrafluoroborate complex in methylene chloride at 25°C. The iminoester units are reduced to tertiary amine units as easily as with sodium borohydride in ethanol at 0°Ci_ to 25°C.

Step- 2C - Reductive methylation

In this method, the polymer VI where R' is hydrogen is heated with a mixture of more than. one equivalent each of formamide and formic acid, and then treated with an aqueous acid and evaporated to dryness under reduced pressure to give the polymer:

where Rg, Q, Z, R', m and n are as (Above angxtt.

The polymer to be subjected to reductive methylation is added to a mixture of 97-100%-g formic acid, preferably 38%-g aqueous formaldehyde, and the reaction mixture is heated at

30 - 100° C- for 20 - 100 hours. Although higher reaction temperatures

is not excluded, the increased rate of thermal decomposition of formic acid, and the risk of degradation of the polymer, make the use of higher temperatures less attractive. The mixture is then treated with an aqueous mineral acid, preferably hydrochloric acid, and the excess of formic acid, formaldehyde and mineral acid is removed by evaporation under reduced pressure.

Step 3 - Direct methylation

Polymer VII where m is 0 is directly methylated by heating the polymer in a mixture of more than one equivalent each of formaldehyde and formic acid under conditions set forth in step 2C to give polymer IX where R 5 , Q, Z, R—, m and n are as stated above.

Step 4 - Addition of R^ and R^ to Polymer VII

For polymers of formula X where R3 and R4 are equal, polymer VII where m is 0 is treated with an excess varying from 1.5-8 equivalents, and preferably 4 equivalents, of an alkylating agent RX in an inert solvent at temperatures from 30 tii 100° C. The reaction is carried out by dissolving the polymer in an inert. solvent such as alcohols, ketones or dimethylformamide. Preferred solvents include methanol, acetone and dimethylformamide, and preferred temperatures are between 50°C and 75°C.

This results in a polymer of formula X where A, Q, Z, RX and n are as above, and m is 1, and Z~ is X . Treatment of polymer X with exactly one equivalent base yields polymer X where m is 0.

For polymers of formula X where R 3 and R 4 are different, polymer VII where m is 0 is treated with less than an equivalent amount of an alkylating agent R 3 X and then, after neutralization with a corresponding equivalent base, the intermediate is treated with sufficient R 3 X for complete alkylation. Both reactions are carried out in an inert solvent at temperatures from 30° C to 100° C. The reactions are carried out by dissolving the polymer in an inert solvent such as alcohols, ketones or dimethylformamide. Preferred solvents include methanol, acetone and dimethylformamide, and. preferred temperatures are between 50° C and

7 5, o C. Acid neutralization gives polymer X where A, Q, Z, R x and n are as above, and m is 1, and Z is X .. Treatment of polymer X with exactly one equivalent base provides. polymer X where m is 0.

Step 5 - Quaternization - Addition of R-^,

Polymer VIII from step 2B, polymer IX from step 2C or step 3, or polymer X from step 4, generally obtained as their acid addition salts (m = 1), is converted to the free base form (m = 0) by treatment with an equivalent amount base. At this stage it is convenient, although not necessary, to remove any inorganic salts by ultrafiltration methods. This has the further advantage of also eliminating any other unwanted low-molecular substances. - The aqueous solution of the polymer is then evaporated under reduced pressure and the product is dried before the quaternization reaction that leads to polymers of formula I. The quaternization reaction is carried out in an inert solvent such as an alcohol, ketone or dimethylformamide. Methanol, acetone and dimethylformamide are preferred solvents. The quaternizing agents are usually halide-containing compounds, preferably grom compounds; but other alkylating agents such as toluenesulfonate esters or trichloromethylsulfonate esters can also be used. When R 1 and R 2 are equal, a reasonable excess of the alkylating agent RX is used; and when R₂ and R₂ are different, the polymer is first treated with a limited amount (5-95% of dat equivalent) of R₂X. After the reaction is complete, the product is treated with an excess of the reagent R2X- When the alkylation reactivities of the reagents R2X and R2X are equal, the reaction can be carried out in a mixture of R2X and R2X in a single step. R₂X and R₂X can be simple alkyl halides and can also have other functional groups that do not intervene disturbingly in the quartering reaction. A simple but by no means exhaustive list of acceptable quaternization reagents includes haloalkyl acid esters, haloalkyl acid amides, haloketones, fluoroalkyltrichloromethylsulfonates, alkylhalohydrins, aralkyl halides, ammonium alkyl halo<genides, lower alkyl-substituted ammonioalcs .yl halides, alkoxyalkyl halides, alkylthioalkyl halides, allyl halides and propargyl bromide.

The reaction is usually carried out by heating a solution of the polymer and the alkylating agent in methanol, acetone or dimethylformamide at 35° C - 10.0° C for 3 - 16 hours. With particularly reactive alkylating agents, a reaction temperature of 50° C is used. The product is isolated, usually directly by filtration, but in some cases it is necessary to dilute the reaction mixture with several volumes of ether before filtration. The product is usually partially dried, ground to a powder and then dried under reduced pressure at temperatures from 25°C to 60°C.

Step 6 - Ion Exchange

The anions of polymer I are generally limited to halide by the methods in the preceding steps. The full range of polymers where the anion Z~ is different from halide can be obtained by dissolving polymer I with a halide anion in water, alcohol or mixtures thereof, in any ratio and passing the solution through a layer of anion exchange resin , either a synthetic or a zeolite type, where the halide ion is exchanged and replaced by Z~. The anion exchange method without the use of a resin method can be direct, i.e. replacement of the halide ion with Z , or one can first replace the halide ion with OH~, and then either by a subsequent ion exchange or simple neutralization replace OH~ with Z .

Moreover, chemical recovery methods can be used when a metal of a metal halide is less soluble than the added metal salt MZ. - The precipitated metal halide can then be filtered from the soluble polymer I.

A simple example of the latter method involves treating a solution of polymer I containing the bromide moiety with an excess of freshly precipitated silver chloride. After the halide anion exchange is complete, the mixture of silver chloride and silver bromide is removed by filtration leaving a solution of polymer I containing the chloride moiety. Alternatively, polymer I where Z is sulphate can be treated with. solutions of water-soluble calcium or barium salts. Thus, sulphate can be replaced with nitrate and the precipitated barium sulphate removed.

Example 1

Poly- f (formimino)-eth yl en )-

A solution of 44 g of A 2-oxazoline and 870 mg of freshly distilled boron trifluoride etherate in 175 ml of purified dimethylformamide was placed in a pressure reactor containing a glass liner and the system was flushed with nitrogen. The mixture was heated at 80° C. for 5 hours and then diluted with methanol and filtered to give 30 g of the poly-((formimino)-ethylene) polymer. In a 5 hour reaction period at 80° C. and boron trifluoride etherate catalyst in a 0.01 molar ratio to A 2-oxazoline, the yield of solid polymer was in the range from 13.2% to at least 68%.

Example 2

Poly-f(formimino)-ethylene)

A solution of 217 g (3.06 mol) A<2->oxazoline and 4.6 g (0.03 mol) of trifluoromethylsulfonic acid in 800 ml of purified dimethylformamide in a sealed tube and under nitrogen atmosphere was heated at 90° C. and stirred in 5 hours.'After cooling, the mixture was diluted with 1200 ml of anhydrous methanol and the product was isolated by filtration. The product was washed with methanol and then with ether before drying under reduced pressure. This reaction gave 150 g of poly-((formimino)-ethylene)-.

Example 3

Poly-f(acetimino)-ethylene)

A 1 g sample of 2-methyl-A 2-oxazoline was introduced into a Carius combustion tube with two drops of boron trifluoride etherate (48%)• The tube was carefully flushed with nitrogen, flame-sealed and placed in a tube furnace at 160°C for 20 hours. The poly-((acetimino)-ethylene) polymer is a glassy, almost colorless resin with a melting range of 155 - 175° C. The polymer is easily soluble in methylene chloride.

Example 4

Poly-f(butyrimino)-ethylene):

In this example, an N-acylethyleneimine is polymerized using a single catalyst system which also causes: conversion to an oxazoline intermediate.

10 ml of N-butyrylethyleneimine and 0.05 ml of boron trifluoride etherate in an evacuated tube were heated at 60° C. for 4 hours. The solid formed was dissolved in 100 ml of chloroform, filtered by adding petroleum ether, redissolved in chloroform and filtered again with petroleum ether. The precipitate was dried giving 6.3 g of poly-{(butyrlmino)-ethylene) with a reduced viscosity of 0.16 in a 1% solution in benzene, and melting point 150°C.

Analogously, but using:

N-benzoylethyleneimine

2-isopropyl-A 2-oxazoline

2-cyclohexyl-A<*2->oxazoline

2-naphthyl-A 2-oxazoline

2-p--tclyl-A 2-oxazoline

you got the equivalent

poly-((benzoylimino)-ethylene)

poly-( (isobutyrimino)-ethylene)

poly-((cyclohexanoylimino)-ethylene)

poly-((naphthoylimino)-ethylene)

poly-((toluoylimino)-ethylene)

Example 5

Poly-((benzoylimino)-ethylene)

-3

1.1322 g (7.60 x 10 mol) of 2-phenyl-2-oxazoline was introduced

-5

in a Carius combustion tube with 7.69 x 10 mol boron trifluoride in the form of a dimethoxyethane solution. After evacuation, flushing with nitrogen and sealing, the sample was heated at 150° C. for 2 hours. 1 g of the light yellow glassy polymer formed was ground to a fine powder and dissolved in 25 ml of methylene chloride. This solution was added to 75 ml of n-hexane, which was stirred vigorously, whereby a thick, white precipitate was obtained. The material was filtered and again filtered two more times in the same way, whereby a fine, white powder was obtained. The recovery of purified poly((benzoylimino)-ethylene) polymer was 80%. The molecular weight of this polymer was 7500.

Example 6

Copolymerization of equimolar mixtures of 2-phenyl-2-oxazoline

and other 2-substituted-2-oxazolines

Equimolar monomer concentrations of 2-phenyl-2-oxazoline and 2-benzyl-2-oxazoline, respectively; 2-methyl-2-oxazoline; and 2-iso-propyl-2-oxazoline at concentrations of 1.5 mol/liter in N,N-dimethyl-acetamide were each heated at 135° C. for approx. 2 hours in use, of 2-phenyl-2-oxazolinium perchlorate as initiator. The poly/- ((acyliarino).-ethylene)--copolymers formed..were ^random with respect to the content of. N-acyl groups.. 2-phenyl-2-oxazoline leads to the formation of the N-benzoyl derivative, 2-benzyl-2-oxazoline forms the N-phenyl-acetyl derivative and the 2-methyl-analog forms the N-acetyl derivative . The composition of the copolymer with respect to the degree of randomness is affected by the relative reaction rates of the various monomers. As the polymers formed can be for the production of linear poly-(ethyleneimine), the composition of the different acyl groups is of no importance because the acyl groups are removed by hydrolysis.

They can of course be reduced directly as described in a subsequent section

.Example.

Example 7

Poly-(iminoethylene)

The hydrolysis of a poly-((acylimino)-ethylene) is carried out by acid or base hydrolysis. (a) As an illustration of base hydrolysis, a solution of 3 g of poly-((formimino)-ethylene) and 3 g of sodium hydroxide in 35 ml of water is heated with stirring at 98° C. for 3 hours. The solution is cooled to room temperature and the white solid which precipitates is isolated by filtration, washed thoroughly with water and dried under vacuum, which gives 1.6 g of poly-(iminoethylene). (b). A 1.29 g sample of poly-((acetimino)-ethylene) is added to 50 ml approx. IN sodium hydroxide. The polymer is practically insoluble in base at room temperature, but after boiling under reflux for 2 6 hours the reaction mixture becomes homogeneous. Cooling to room temperature causes the reaction mixture to gel to a white mass. The hydrolysis" is about 65% complete. The non-acylated" poly-(iminoethylene) is purified by repeated distillation, i.e. dissolution in acid, filtration of partially acetylated poly-(iminoethylene) and neutralization of the filtrate. (c) A lg sample of poly-((acetimino)-ethylene) was dissolved in 50 ml IN sulfuric acid. A homogeneous mixture was obtained which was heated under reflux for 3.5 hours, the smell of the hydrochloric acid becoming noticeable. After at this time, titration of a sample with 1N sodium hydroxide showed 27% complete hydrolysis.After 21 hours of reflux, hydrolysis was 38% complete.

In general, an essentially complete hydrolysis is obtained by carrying out the hydrolysis as above, but in a closed vessel]: by

120° C, or higher, temperatures.

Poly-i (acylimino).-ethylenes} are reduced to N-alkyl and N-aralkyl derivatives without prior hydrolysis to the free base. The preferred reducing agent is diborane as in the following example. Lithium aluminum hydride, lithium trimethoxy aluminum hydride can also be used.

Example 8

Poly-(ethylimino)-ethylene

To a solution of 200 ml (3 34 mmol) 1.67 M diborane in tetrahydrofuran in a 500 ml flask equipped with a reflux condenser, dropping funnel, magnetic stir bar and kept under nitrogen is added 17 g (200 mmol/monomer unit) poly-((acetimino)- ethylene) in 100 ml of tetrahydrofuran during 15 minutes. The temperature is kept at approx. 0° C during the addition. The reaction mixture is then kept under reflux for 6 hours. The mixture is allowed to cool to room temperature and 50 ml of 6M hydrochloric acid is added slowly through a dropping funnel. The tetrahydrofuran is removed by distillation at atmospheric pressure as hydrogen is evolved (15.5 1, 0.6 mol) from the hydrolysis of the amine-borane complex. Sodium hydroxide is added to precipitate poly-((ethylimino).-ethylene) .

Analogously, each of the polymers obtained in

example 4 to give respectively:

poly-((benzylimino)-ethylene),

poly-[(isobutylimino)-ethylene),

poly-((naphthylmethylimino)-ethylene).

Example 9

Poly- f ( methylin nino) - ethylene hydrochloride)

2.5 g of poly-(iminoethylene) is added slowly to 12 g

90% formic acid and 5.5 g of 38% aqueous formaldehyde are added.

After the mixture has been heated at 100° C. for 72 hours, it is cooled and 5.5 ml of concentrated hydrochloric acid is added. The mixture is evaporated to dryness under reduced pressure, which gives 5 g of poly((methylimino)-ethylene hydrochloride}.

Example 10

Poly- ((dimethyl imino) - ethylene- chlorold)-

50.0 mg (5.4 mmol) of poly-((methylimino)-ethylene hydrochloride) is dissolved in 50 ml of methanol containing 291 mg (5.4 mmol) of sodium

methoxyd. The solution is cooled in an acetone-dry ice bath, and 10 g of methylene chloride is condensed in the solution. This mixture is heated in a sealed tube at 80° C for 5 hours. This mixture is evaporated to dryness under reduced pressure, and the product is taken up in 3 ml of anhydrous methanol and filtered, and the solution is evaporated to dryness. Dissolution of the product in methanol, filtration followed by evaporation to dryness is repeated several times. The filtrate is evaporated under reduced pressure, which gives 400 mg of poly-((dimethylimino)-ethylene chloride).

Example 11

Poly-(dimethylimino)-ethylene bromide

A solution of 860 mg (20 milliequivalents) of poly-(iminoethylene) in 30 ml of methanol is treated with 9.5 g (100 mmol) of methyl bromide at 50° C. for 3 hours. The reaction mixture is evaporated to dryness under reduced pressure. The residue is treated with 1.08 g (20 mmol) of sodium methoxide in 10 ml of methanol and evaporated to dryness. The residue is taken up in 30 ml of anhydrous methanol and treated with 9.5 g (100 mmol) of methyl bromide, and the solution is heated at 50° C. for 3 hours. After evaporation, the product is taken up in water, and the solution is subjected to ultrafiltration through a "VM 2 Diaflo Ultrafilter". The retentate is then evaporated under reduced pressure, which gives 2.8 g of poly-((dimethylimino)-ethylene bromide}).

Example 12

Poly-((dimethylimino)- ethylene methosulfate)

0.5 g of poly-((methylimino)-ethylene hydrochloride) is dissolved in 50 ml of methanol containing 0.29 g of sodium methoxy. The solution is evaporated to approx. 20 ml and 0.7 g of dimethylsulphate are added. The solution is then heated for 6 hours at 50° C., and the product precipitated by pouring the solution into a large volume of acetone or by evaporating the methanol followed by acetone washing. The product is dried at room temperature under reduced pressure.

Example 13

Poly- f{( 2- hydroxyethyl)- methylimino}- ethylene- chloride)

The procedure in example 10 was followed, but 15.8 g of ethylene chlorohydrin was used instead of 10 g of methyl chloride. The mixture was heated at 80° C. for 5 - 7 hours and then freed from solvents and excess reagents by stripping under

O

ne.ds.that pressure...The residue was .poly-(f.(2-hydroxyethyl.)-methylimino)-ethylene-chloride) .

Analogously, a is used. equivalent amount of propylene chlorohydrin. or sec-propylene chlorohydrin instead of ethylene chlorohydrin, which gives poly-({.(1-methyl-2-hydroxyethyl)-methylimino)-ethylene chloride)- and poly-({((2-liydroxypropyl)-methylimino)-ethylene chloride)-.

Example 14

Poly- { ( 2- hydroxyethylimino)- ethylene)

0.5 g of poly-(iminoethylene) from example 7 is dissolved in 50 ml of methanol and heated with 0.35 g of ethylene oxide in a sealed tube under nitrogen at 60° C. for 3 hours. The solvent and excess epoxy are removed by stripping under reduced pressure. The residue was poly-((2-hydroxyethylimino)-ethylene).

Example 15

Poly- f{( 2- hydroxybutyl)- 2- hydroxyethylimino)- ethylene- bromide)

Poly-((2-hydroxyethylimino)-ethylene) from the previous example is heated in 50 ml of acetone with 20 g of 2-hydroxybutyl bromide at 80 - 90° C in a* sealed tube for 6 - 8 hours.

The product is recovered - as before by removing solvent and excess reagent under reduced pressure. The residue is poly-({(2-hydroxybutyl)-2-hydroxyethylimino)-ethylene bromide).

Example 16

Poly-/(methylimino)-ethy. lin-hydrochloride"!

A mixture of 25 g of poly-(formiminoethylene), 504 g of 97-100% formic acid and 118 g of 38% aqueous formaldehyde (formalin) was heated at 100° C. for 60 hours. The reaction mixture was cooled, 210 ml concentrated hydrochloric acid was added and the mixture was evaporated to dryness under reduced pressure at 50 C. The product is washed with methanol and then ether, and dried, thereby obtaining 34.6 g of poly-r(methylimino)-ethylene hydrochloride.

Example 17

Poly-'(methylimino)-ethylene/

A solution containing 0.325 mol of sodium hydroxide is prepared by dissolving 17.55 g of sodium methoxide in 400 ml of water. To this is added 28.6 g (0.31 mol) poly-^(methylimino)-ethylene-hydrochloride], and the total volume of the solution is brought up to 500 ml by adding water. The solution is then desalted and is also exempt from any product with .en. molecular weight of less than 1000 using a. "Amicon." filter cell equipped with a "UM2 Diaflo Ultrafilter.", The solution is then evaporated under reduced pressure at 50° C. which gives 16 g of poly-((methylimino)-ethylene}.

Example . 18

Poly-f(dimethylimino)-ethylene bromide}

A solution of 21.7 g (0.38 mol) of poly-[(methylimino)-ethylene} in 130 ml of anhydrous methanol is cooled and 364 g (3.8 mol) of condensed methyl bromide is added. The mixture in a glass-lined pressure reactor is heated by 50° C for 5 hours. After the mixture has cooled, the product is isolated by filtration, washed with ether and dried under reduced pressure, thereby obtaining 58 g of poly-((dimethylimino)-ethylene bromide).

Example 19

Poly- f ( dimethylimino)- ethylene- chloride)-

A solution of 58 g of poly-((dimethylimino)-ethylene bromide)

(0.38 mole) in 3 liters of water is passed slowly (10 ml/min) through a 770 ml column of 2 00 - 4 00 mesh "AG1-X8" quaternary ammonium chloride resin (1078 milliequivalents of Cl~). After 4200 ml of effluent had been collected, it was evaporated under reduced pressure at 50 - 55° C, and dried

whereby 37 g of poly-((dimethylimino)-ethylene chloride)'■ was obtained.

Example 20

Production of poly-((dimethylimino)-ethyl en-ascorbate)

5.0 g of poly-(dimethylimino)-"ethylene chloride" is dissolved in 75 ml of distilled water and passed through a column containing 100 g (0.5 mol Cl exchange capacity) of a polystyrene resin, in which the benzene ring is substituted with 4- oxotrimethylammonium hydroxide ("Bio Rad AG 1 x 8"). Six column volumes of eluate (450 ml) containing poly-((dimethylimino)-ethylene hydroxide) were collected, evaporated to 150 ml, cooled to 15°C and neutralized with 8.8 g (0.05 mole) of ascorbic acid, U.S.P. The clear neutralized solution was then shell-frozen and lyophilized to give a white solid which was easily pulverized.

The other polymers according to the invention can likewise be transferred to the ascorbate salt, or by using other acids containing physiologically acceptable anions instead of the ascorbic acid,

other salts are obtained as described above1..

Example 21

5, 6- dlh:ydro- 4H- T, 3- oxazine

A mixture of 94 g (1.13 mol) t-butyl iscnitrile, 85 g (1.13 mol), freshly distilled 3-aminopropanol, and 7.4 g (0.055 mol) silver cyanide was stirred at 90° C. under a blanket of nitrogen in 16 hours. The product was isolated from the reaction mixture by distillation at 45 mm and then purified by repeated fractionation. Usually two such fractionations are sufficient to give a pure product. In this way, 44 g of pure 5,6-dihydro-4H-1,3-oxazine, boiling point 58°C/58 mm, nD 1.4485 are obtained, and are stored over molecular sieves type 4A and under nitrogen.

Example 22

Poly-((formimino)-trimethylene)

A solution of 44 g (0.52 mol) of 5,6-dihydro-4H-1,3-oxazine in 140 ml of purified dimethylformamide is placed in a pressure tube and 1.52 g (0.011 mol) of iodomethane is added . The system is flushed with nitrogen, sealed and heated with wood. 80° C for 5 hours. The mixture is cooled and diluted with ten volumes of ether, and the product is isolated by filtration. The product is washed with ether. and dried under reduced pressure at 75° C, which gives 40 g of poly(formimino)-trimethylene, melting point under sp.altning 111 112° C.

Example 2 3 ;

Poly(methylimino)trimethylene hydrochloride)

A mixture of 53 g of poly-(formiminotrimethylene), 1320 g

97 - 100% formic acid and 308 g of 38% aqueous formaldehyde are heated at 100° C. for 120 hours. After the solution has cooled, 650 ml of concentrated hydrochloric acid are added, and the mixture is evaporated to dryness at 50° C. under reduced pressure. The residue is triturated with 400 ml of methanol, isolated by filtration, washed with ether and dried under reduced pressure, which gives 67 g of poly-((methylimino)-trimethylene hydrochloride)-.

Example number 24

Poly- ( methyiimiho). -trim ethyl len

A solution of 67 g (630 milliequivalents) of poly((methylimino),-trimethylene-hydrochlorid)- in 600 ml of water is treated with 39 g (0.72 mol), sodium methoxyd. This is simply an easy way of preparing a solution of sodium hydroxide of exact normality. An equivalent volume of a standardized solution of sodium hydroxide is equally suitable. The solution is desalted and polymer with a molecular weight below 1000 is removed using an "Amicon" filter cell equipped with a "UM2 'Diaflo Ultra filter". Finally, the solution is evaporated at 50° C under reduced pressure, which gives 45 g of poly-((methylimino).-trimeth<y>lene}.

Example 25

Poly(dimethylimino)- trimethylene- bromide)

A solution of 14 g (200 milliequivalents) of poly-((methylimino)-trimethylene} and 76 g (0.8 mol) of bromomethane in 90 ml of methanol is heated at 50° C. in a sealed reactor for 5 hours. The product is isolated by filtration, washed with methanol and then with ether, and dried under reduced pressure which gives 28 g of poly-((dimethylimino)-trimethylene bromide}).

Example 2 6

Poly-f(dimethylimino)-trimethylene- chloride)

A solution of 28 g (170 milliequivalents) of poly-((dimethylimino)-trimethylene bromide) in 1400 ml of water is passed slowly through a column containing 1000 ml of "Dowex 1-X2" (Cl~ form) resin (0.8 mol) . After the solution has passed through, water is passed through the column until the effluent gives a negative silver nitrate test. The total effluent is evaporated to dryness, and the product is dried under reduced pressure, which gives 17.2 g of poly-((dimethylimino)-trimethylene chloride}.

Example 27 '" ; Poly-f{methyl-(3-hydroxypropyl)-imino}-trimethylene-bromide)

A solution of 142 mg (2 milliequivalents) of poly-((methylimino)-trimethylene) and 1.12 g (8 mmol) of 3-bromopropanol in 5 ml of purified dimethylformamide is heated at 75° C. for 24 hours. The product is isolated by filtration, washed with acetone and dried under reduced pressure, which gives 330 mg of poly[{methyl-(3-hydroxypropyl)-imino}-trimethylene bromide}.

Example 28

Poly-{(meth yl'-'^^(:3-hydroxypro py 1)- imino' )-trimeth y len- chlor id

A solution of 315 mg 41/5 milliequivalents) poly-

(Imethyl-(3^hydro.xyprapYl)..Timino}trim in .16 ral water is passed slowly through a column of 9 ml "Dowex 1-X2" ion exchange resins (7.2 mmol chloride ion) , and then water is passed through until the effluent gives a negative sample, for chloride ion. The combined effluent is evaporated to dryness at 50° C. under reduced pressure which gives 230 mg of poly-({methyl-(3-hydroxypropyl).-imino)- trimethylene chloride} .

In the preceding example, a polymer is produced with formula III wherein R 1 and R 2 are both 3-hydroxypropyl. The following three examples will show how polymers of formula III can be prepared with R 1 = 3-hydroxypropyl and R 2 = CH 2 . In these examples, R 1 and R 2 constitute respectively 5 - 95% and 95 - 5% of the sum of R 1 + R 0 , and are distributed randomly along the polymer chain.

Example 29

Polymer with formula III where R^= 3-hydroxypropyl and R2~methyl

(random distribution in a 5:95 ratio)

A solution of 462 mg (6 milliequivalents) of poly-((methylimino)-trimethylene) and 41 mg (300 umol) of 3-bromopropanol in 12

ml of dimethylformamide is heated at 75° C. for .24 hours. The mixture is cooled and 2.9 g (30 mmol) of methyl bromide are added. The reaction mixture. heated at 50° C. for 3 hours. The product is isolated by evaporating the reaction mixture under reduced pressure and then washing with ether and drying under reduced pressure. Exchange of the bromide ion with the chloride ion is carried out; .in the usual manner using an ion exchange resin'as described above..

Example 30

Polymer of formula III where R 2 = 3-hydroxypropyl and R 2 =

methyl (random distribution in a 50:50 ratio)

A solution of 213 mg (3 milliequivalents) of poly-((methylimino)-trimethylene) and 209 mg (1.5 mmol) of 3-bromopropanol is heated at 75° C. for 24 hours. The reaction mixture is cooled and 1.5 g of methyl bromide is added. The reaction mixture is heated at 50° C. for 3 hours and then worked up in the manner described above.

Example 31

Polymer of formula III where R^= 3-hydroxypropyl and R2=

methy l (random distribution - in a 95:5 ratio)'

A solution of 142 mg (2 milliequivalents) of poly-((methylimino)„-trimethylene} and 264 mg (1.9 mmol). 3-bromopropanol is heated at 75° C. for 16 hours. After the mixture has cooled, add 1 g of methyl bromide and the mixture is heated at 50° C for 12 hours. The reaction mixture is worked up in the manner described above.

Example 32

P oly~ f {methyl - ( 3-methoxypropyl) - imino) - tri ime thy 3. en-chlor id}

A solution of 284 mg (4 milliequivalents) of poly-((methylimino),-trimethylene) and 2.45 g (16 mmol) of 3-methoxypropyl bromide in 15 ml of dimethylformamide is heated at 75° C. for 16 hours. The product is isolated by filtration, washed with ether and dried under reduced pressure. The product is dissolved in 25 ml of water and the bromide ion is exchanged with chloride ion by ion exchange as described above. In this way, 450 mg of poly-({methyl-(3-methoxypropyl)-imino}-trimethylene chloride) are obtained.

For the synthesis of polymers of formula III where R± and R2 are respectively 3~methoxypropyl and methyl in ratios varying from 5:95 to 95:5, the procedure is essentially as described above where poly((methylimino)-trimethylene) is reacted with one limiting amount of 3-methoxypropyl bromide and then with an excess of methyl bromide.

Example 3 3

Poly-(Oflathyl-(3-methylthiopropyl)-imino}-trimethylene chloride).

A solution of 426 mg (6 milliequivalents) of poly-((meth<y>limino)-trimeth<y>lene) and 4.06 g of 3-methylthiopropylformamide in 15 ml of dimethylformamide is heated at 75° C. for 24 hours. The product is isolated by filtration, taken up in 30 ml of water and passed through a ■ column with 45 ml of "Dowex 1-X2" ion exchange resin (36 mmol of chloride ion). Evaporation of the aqueous eluate gives 650 mg of poly({methyl-(3-methyl-thiopropyl)-imino-trimethylene chloride).

For...the synthesis of polymers of formula III where R-^ and R2 are respectively 3-methylthiopropyl and methyl in ratios varying from 5:95 to 95:5, the procedure is essentially as described above where poly-((methylimino)- trimethylene) is reacted with a limiting amount of 3-methylthiopropyl bromide and then with an excess of methyl bromide.

Example 34

Poly-f{ methyl-(3-aminopropyl)-iminox-1rimethy1ene-dichlorind)

A solution of 568 mg (8 milliequivalents) of poly-((methyl imino).-trimethylene) and 8.6 g (30 mmol) of 3-phthalimidopropyl bromide in 25 ml of dimethylformamide is heated at 75°C for 18 hours . The product is isolated, by filtration, suspended in 10 ml of methanol and treated with 1 g of anhydrous hydrazine at 50° C. for 3 hours. The mixture is evaporated under reduced pressure, acidified with dilute hydrochloric acid, triturated with ether and isolated by filtration. The product is taken up in water and passed through a 45 ml column with "Dowex 1-X2" ion-exchange resins. (36 mmol chloride ion)... Evaporation of the aqueous eluate gives poly-({methyl-(3-ammoniopropyl)-imino}-trimethylene dichloride}...

Alternatively, a solution of 568 mg (8 milliequivalents) is heated. poly-((methylimino)-trimethylene) and 6.3 g (40 mmol) of l-bromo-3-chloropropane in 20 ml of dimethylformamide at 75° C. for 18 hours. The reaction mixture is evaporated under reduced pressure and heated with

30 ml of liquid ammonia at 50° C for 5 hours. Ammonia is allowed

to evaporate, and the product is transferred to the chloride ion-containing form by passing it through a 45 ml column of "Dowex 1-X2" ion exchange resin in the chloride form. •

For the synthesis of polymers of formula III where R-^ and R2 are respectively 3-ammoniopropyl and methyl in ratios varying from 5:95 to 95:5, the procedure is essentially as described above where poly(methylimino)-trimethylene is reacted with a limiting amount of either 3-phthalimidopropyl bromide or 1-bromo-3-chloroprepane, and then with an excess of methyl bromide.

Example 35 Poly-({methyl-(3-methylammoniopropyl)-imino}-trimethylene dichloride)

A solution of 710 mg (10 milliequivalents) of poly-((methylimino)-trimethylene} and 8 g of 1-bromo-3-chloropropane in 30 ml of dimethylformamide is heated at 75° C. for 16 hours. The mixture is evaporated under reduced pressure, suspended for 10 ml of methanol and treated with 3 g of methylamine at 50° C in a sealed tube. The reaction mixture is evaporated under reduced pressure, taken up in water and passed through a 50 ml column with "Dowex 1-X2" ion exchange resin to obtain the desired product.

For the synthesis of the polymer of formula III where R-j_ and R2 are respectively 3-methylammoniopropyl and methyl in ratios varying from 5:95 to 95:5, the procedure is essentially the same as described above where poly-((methylimino)-trimethylene )- is first reacted with a limiting amount of 1-bromo-3-chloropropane and then with an excess of methyl bromide.

Example 36.

P o ly- ({met.iiy.t~( 3-' d . ime t hyl ' ammohiopr opy 1) - imi no} tr' ime thy 1 en - d i k 1 or i d)

A solution of 710 mg (10 milliequivalents) of poly-((methylimino).-trimethylene} and 7.9 g of 1-bromo-3-chloropropane in 35 ml of dimethylformamide is heated at 75° C. for 16 hours. The mixture is evaporated under reduced pressure, suspended in 10 ml of methanol and treated with 2.3 g (50 mmol) of dimethylamine in a sealed tube at 50° C. The reaction mixture is evaporated under reduced pressure, taken up in water and passed through a 50 ml column with "Dowex 1-X2" ion exchange resin (40 mmol chlorine ion) which gives poly-({methyl-(3-dimethylammoniopropyl)-imino}-trimethylene dichloride}.

Alternatively, a solution of 710 mg (10 milliequivalents) of poly-((methylimino)-trimethylene) in 35 ml of dimethylformamide is treated with 6.6 g (40 mmol) of 3-dimethylaminopropyl bromide at 50° C. for 6 hours. The product is isolated by filtration, taken up in water and passed through a 50 ml column of "Dov/ex 1-X2" ion exchange resin (40 mmol chloride ion) which gives the 3-dimethylammoniopropyl analogue above

For the synthesis of polymers of formula III where R-^ and R2 are respectively 3-dimethylammoniopropyl and methyl in ratios varying from 5:95 to 95:5, the procedure is essentially as described above where poly-((methylimino)-trimethylene) is treated with either a limiting amount of 1-bromo-3-chloropropane or 3-dimethylaminopropyl bromide, and then with an excess of methyl bromide.

Example 37

Poly-({methyl-(3-trimethylammoniopropyl)-imino}-trimethylene-dibromide)

A solution of 710 mg (10 milliequivalents) of poly-((methylimino)-trimethylene} and 10.4 g (40 mmol) of 3-bromopropyltrimethylammonium bromide in 40 ml of purified dimethylformamide is heated at 75° C. for 12 hours. The product is isolated by filtration , washed with acetone and dried under reduced pressure, which gives 1.8 g of poly-({methyl-(3-trimethylammoniopropyl)-imino}-tri ime thylene dibromide)- .

Example 38

Poly-({methyl-(3-trimethylammoniopropyl)-imino)- trimethylene dibromide]

A solution of 1.66 g (5 milliequiv.) of poly-({methyl-(3-trimethylammoniopropyl)-imino}-trimethylene dibromide) in 85 ml of water is passed slowly through a column containing 50 ml (40 mmol) of "Dowex I-X 2." resin in the chloride ion form. : Water is then passed through until no chloride ion can be detected in the eluate. Evaporation of the combined eluate to dryness at 50°. C provides. 1.1 g of poly-({methyl-(3-trimethylammoniopropyl 1-imino}-trimethylene dichloride).

For the synthesis of polymers of formula III where and R2 are respectively -' 3-trimethylammoni.opropyl and methyl in ratios varying from 5:9.5 to 9.5:5, the synthesis i. is essentially as described above in, example 37 where ' poly- -(methylimino)-trimethylene} is reacted with a limiting amount of 3-bromopropyltrimnethylammonium bromide and then with an excess of methyl bromide.

Example 39

Poly-({meth yl-(carboethoxymethyl)-imino}-trimethylene- chloride. d)

A solution of 1 g (14 milliequiv.) poly-((methylimino)-trimethylene) and 8.8 g (56 mmol) ethyl-a-bromoacetate in 20 ml of dimethylformamide is heated at 50° C. for 12 hours. The mixture is diluted with five volumes of ether and the product is isolated for filtration. The product is taken up in water and passed through a 7 5 ml column with "Dowex 1-X2" ion exchange resin (SO mmol chloride ion) and the eluate is evaporated under reduced pressure whereby poly-({ methyl-(carboethoxymethyl)-imino}-trimethylene chloride) .

Example 40

Poly-({ methyl-( c. rbor. y latomethy 1)- imino}- trimethylene)

A solution of 500 mg (7 milliequiv.) poly-((methylimino)-trimethylene} and 4.4 g (28 mmol) ethyl-α-bromoacetate in 10 ml purified dimethylformamide is heated at 50° C. for 12 hours. The reaction mixture is evaporated to dryness under reduced pressure, and the residue is treated with 28 ml 1N sodium hydroxide overnight. Then 21 ml 1N hydrochloric acid is added to the mixture and the solution is desalted in an "Amicon", filter cell equipped with a "UM2 Diaflo Ultrafilter". The solution is evaporated to dryness at 50 ° C which gives 650 mg of poly-({methyl-(carboxylatomethyl)*-imino}-trimethylene).

For the synthesis of the polymer of formula III where R 1 and R 2 are respectively carboxylatomethyl and methyl in ratios varying from 5:95 to 95:5, the procedure is essentially as described above where poly-((methylimino)-trimethylene) is reacted with a limiting amount of ethyl-α-bromoacetate and then with an excess of methyl bromide.

Example 41. ,, .....

Pqly-'( {roe thyl-( carb

One. solution of 355 mg (5 milliequivalents) of poly-((methylimino 1-trimethylene) and 3.5 g (25 mmol) of 2-bromoacetamide in 10 ml of dimethylformamide is heated at 60°C for 15 hours. The product is isolated at filtration, taken up in water and passed through a 25 ml column with "B.owex 1-X2" ion exchange resin (20 mmol chloride ion) which gives poly-({methyl-(carbamylmethyl)-imino}-trimethylene chloride) .

For polymers of formula III where R-^ and R2 are respectively carbamylmethyl and methyl in ratios varying from 95:5 to 5:95,

is the process essentially as described above where poly-((methylimino)-trimethylene} is first treated with a limiting amount of 2-bromoacetamide and then with an excess of methyl bromide.

Example 4 2

Poly-{{methyl-(3-N^-methylcarbamidinopropyl)-imino}-trimethylene-• chloride- hydrochloride) '

A solution of 719 mg (10 milliequivalents) of poly((methylimino)-trimethylene)- and 12.5 g (40 mmol) of 4-bromo-N<2->methyl.1-N-benzyloxycarbonylbutyramide in 50 ml of dimethylformamide is heated at 75° C. for 16 hours. The mixture is evaporated under reduced pressure and the product is extracted in water. The aqueous solution is acidified to pH 3 with hydrochloric acid, hydrogenated over a 5% Pd/carbon catalyst, filtered and passed through a 100 ml column with "Dowex 1-X2" ion exchange resin (80 mmol chloride ion), which gives the desired product containing chloride- the motion.

For compounds of formula III where R^ and Rp are respectively 3-N 2-methylcarbamidinopropyl and methyl in a ratio of 95:5 to 5:95, the method described above is used where poly-((methylimino)-trimethylene)- is first treated with a limiting amount of 4-bromo-N^-methyl-N-benzyloxycarbonylbutyryamidine and then with an excess of methyl bromide.

Example 4 3

Poly-({methyl-(3-guanidinopropyl)-imino}-trimethylene chloride hydrochloridej '.. ' '

A solution of 355 mg (5 milliequivalents) of poly-((methylimino)-trimethylene)- and 5.6 g (25 mmol) of N^-3-bromopropyl-N<3->ni.troguanidyl.n . in 15 ml of dimethylformamide is heated at 75° C. for 16 hours. The mixture is evaporated under reduced pressure and the product is extracted in water. The aqueous solution is acidified to pH 3 with hydrochloric acid and hydrogenated in the presence of 100 mg of activated platinum. The solution is filtered and passed through a 50 ml column of "Dpwex 1-X2" ion exchange resin (40 mmol chloride ion), which gives the .desired product containing, the chloride motion.

Compounds of formula III where R-1 and R2 are respectively -3-guanidinopropyl and methyl in ratios varying from 95:5 to 5:95, the method described above is used where poly-(methylimino). -trimethylene is first treated with a limiting amount of N^-3-bromopropyl-N 3 -nitroguanidine and then o with an excess of methyl bromide.

Ek.s.ejnp tf,1,.,,. 4 4

Poly-f{methyl-(2-oxopropyl)-imino}-trimethylene- chloride)

A solution of 355 mg (5 milliequivalents) of poly-((methylimino).-trimethylene} and 2.3 g (25 mmol) of chloropropanone-2' is heated at 50° C. for 16 hours. The product is isolated by filtration, triturated with ether and dried under reduced pressure.

For polymers of formula III where R and R are respectively 2-oxopropyl and methyl in ratios varying from 95:5 to 5:95, the above-described procedure is followed where poly-((methylimino)-trimethylene) is first treated with a limiting amount of chloropropanone-2 and then with an excess of methyl bromide. Treatment of the product with "Dowex 1-X2" in the chloride form gives the product containing only the chloride ion.

. Example 45

Poly-f{methyl-(benzyl)-imino}-trimethylene- chloride)

A solution of 710 mg (IQ milliequivalents) of poly-((methylimino)-trimethylene} and 6.8 g (40 mmol) of benzyl bromide in 15 ml of dimethylformamide is heated at 50° C. for 16 hours. The product is isolated by evaporation of the reaction mixture under reduced pressure and extraction in water.The aqueous solution is passed through a 25 ml column of "Dowex 1-X2" ion exchange resin (40 mmol chloride ion) giving the desired product containing the chloride ion.

For polymers of formula III where R and R are respectively benzyl and methyl, the method described above is followed where poly-(methylimino).-trimethylene is first reacted with a limited amount of benzyl bromide and then with an excess of methyl bromide.

Example 4 6

Poly-f{methyl-(1-propen-3-yl)-imino}-trimethylene- chloride)

A solution of 426 mg (6 milliequivalents) of poly-((methylimino)-trimethylene) and 3.7 g (30 mmol) of 3-bromopropene-1 (allyl bromide) in 12 ml of dimethylformamide is heated at 50° C. for 16 hours. The product is isolated by filtration and dissolved in water. The aqueous solution is passed through a 40 ml column with "Dowex 1--X2" ion exchange resin (32 mmol chloride ion) and the eluate is evaporated under reduced pressure, which gives the desired product containing the chloride ion.

For compounds of formula III where R-^ and R2 are respectively 1-propen-3-yl and methyl in ratios varying from 95:5 to 5:95, the method corresponds to the one described above where poly-((methylimino)-trimethylene) is reacted with a limited amount of 3-bromopropene-1 and then with a shot of methyl bromide.

Example 4 7

Poly-f{methyl-(l-propyn-3-yl)-imino}-trimethylene- chloride)

A solution of 710 mg (10 milliequivalents) of poly_

((methylimino)-trimethylene) and 3.6 g (30 mmol) of 3-bromopropyn-1 (propargyl bromide) in 12 ml of dimethylformamide are heated at 50° C. for 16 hours. The product is isolated by filtration, dissolved in water and passed through a 40 ml column with "Dowex 1-X2" ion exchange resin (32 mmol chloride ion), which gives the desired product containing the chloride ion.

As in the previous examples, polymers of formula III where R-1 is 1-propyn-3-yl and R2 is methyl in ratios varying from 5:95 to 95:5 are prepared by first treating poly-((methylimino)-trxmethylenej with a limited amount of propargyl bromide and then with an excess of methyl bromide.

Example 48

Poly- f{ methyl-( 2, 2, 2- trifluoroethyl)- imino}- trimethylene- chloride)

A solution of 355 mg (5 milliequivalents) of poly-((methylimino)-trimethylene) and 6.2 g (22 mmol) of 2,2,2-trifluoroethyl-trichloromethylsulfonate in 15 ml of dimethylformamide is heated at 50° C.

for 16 hours. The reaction mixture is diluted with ether and the product is isolated by filtration. The product is taken up in water and passed through a 25 ml column with "Dowex 1-2" ion exchange resin (20 mmol chloride ion) and the eluate is evaporated under reduced pressure which gives

desired product containing the chloride motion.

For polymers of formula III where Rj is 2,2,2-trifluoroethyl 1 and R2 is methyl in ratios varying from 95:5 to 5:95, the methods described above are used where poly-((methylimino)-trimethylene} is first treated with a limited amount of 2,2,2-trifluoroethyl-trichloromethylsulfonate and then with an excess of methyl bromide.

Example 4 9

Poly-({meth yl-( 1- - p- glucopyranosyl)-imino}-trimethylen- chloride)

A solution of 535 mg (5 milliequivalents) of poly-((methylimino)-trimethylene} and 10.3 g (25 mmol) of tetra-O-acetyl--ct-D-glucopyranosyl bromide in 25 ml of dimethylformamide is heated at 50° C.

for 16 hours. The product is isolated by dilution with ether followed by filtration. The product is taken up in 5 ml of water and 2 ml of 10% hydrogen bromide is added. After standing overnight, the solution is diluted to a volume of 100 ml with water and placed in an "Amicon" filter cell containing a "UM-2 DiafloUltrafilter". After 800 ml of filtrate has been collected, the residue is evaporated to a volume of 50 ml and passed through a 25 ml column of "Dov/ex 1-X2" ion exchange resin (20 mmol chloride ion). Evaporation of the eluate gives the desired analogue containing the chloride moiety.

For compounds of formula III where R-^ is 1-a-D-glucj-pyranosyl and R2 is methyl in ratios varying from 95:5 to 5:95, the method described above is followed where poly-[(methylimino)-tri-methylenej is treated first with a limited amount of tetra-O-acetyl-α-D-glucopyranosyl bromide and then with an excess of methyl bromide.

The procedures described in Examples 27 to 49 are equally applicable to transfers of poly-((methylimino)-ethylene} to the corresponding quaternary analogues and follow using the corresponding milliequivalents of poly-^(methylimino)-triethylenej instead of poly-( (methylimino)trimethylene) as shown in Example 50.

Example pel 5 0

Poly-({ methyl-( 2- trimethylammonioethyl)- imino}- ethylene dibromide)

A solution of 570 mg (10 milliequivalents) of poly-((methylimino)ethylene) and 9.9 g (40 mmol) of 2-bromomethyltrimethylammonium bromide in 40 ml of dimethylformamide is heated at 75° C. for 12 hours. After cooling, the reaction mixture is diluted with five volumes of ether, and the product is isolated by filtration and dried under reduced pressure.

Effective lowering of cholesterol blood levels is obtained by oral administration of remarkably small doses of the polymers produced according to the invention. This enables flexibility

in the preparation of the preparation which was previously not possible. The polymers can be finely divided powders and can suitably be used as such or preferably mixed with different amounts of solid carriers such as colloidal silicic acid, starches, sucrose, talc, lactose, cellulose or modified cellulose, dry milk powder, protein powders such as soy flour and the like. They are usually provided in unit dose forms such as tablets, filled gelatin capsules or a tin or paper envelope containing the pre-measured dose which may include supplementary vitamins and minerals, and which can be easily torn open and added to edible liquids such as fruit juices or other drinks. The unit dose preparation may comprise from 10 to 99% by weight of polymer, the remainder being carriers, flavourings, excipients, wetting agents and the like. In such a unit dose, the active polymer can amount from 0.1 g to up to 10 g in powder packets.

Also suitable are aqueous solutions or suspensions that can be prepared and to which a sweetener or flavoring agent is preferably added. Although not highly desirable, the polymers can be mixed with various media such as safflower or corn oil for oral administration as such or as an aqueous emulsion. These can also be encapsulated.

As mentioned above, the total daily dose of bile acid-binding polymer is preferably divided into portions and taken before each meal or before bedtime. This administration routine provides maximum resin contact time during periods of highest intestinal bile acid concentrations.

The polymers according to the invention can be used alone, or, if desired, they can be processed together with triglyceride synthesis inhibitors or other bile acid binding agents for special treatments. Moreover, as mentioned above, the spolymers described here form salts with acids of clofibrate and halofenate, which salts are useful in cardiovascular disease therapy. The following examples illustrate the dosage forms that can be used in carrying out the invention. Professionals in the manufacture of pharmaceutical preparations will be aware of variations that can be made without deviating from the invention. It is anticipated that multiple doses, e.g. two or three tablets or capsules can be taken at once if higher doses are prescribed.

Additional ingredients that may include the carrier portion of

■the preparations' according to the invention may also have pharmacological activity and may include other choleretic agents such as tocamfyl-florantyrone; taurine; and glycine; hypocholesteremic agents such as nicotinic acid; The D-isomer of 3,3',5-triiodothyronine; thyroxine-like compounds such as sodium-L-thyroxine and sodium-D-thyroxine; triiodo-thyropropionic acid?naf oxidine hydrochloride.1, 5-methylpyrazole-3-carboxylic acid and 3-methyl-5-isoxazolecarboxylic acid; fecal softeners such as poloxalcol and dioctyl sodium suifosuccinate; as well as unsaturated fatty acids such as linoleic acid, arachidonic acid and linolenic acid; edible vegetable, acids such as corn oil and safflower oil.

Powder packs

Linear, unbranched and non-crosslinked poly-((dimethylimino). -ethylene chloride)- with a molecular weight of approx. 20,000 are finely pulverized

and mixed with 1% by weight of lactose powder. Aluminum envelopes containing a paper bag ring are individually filled with 0.55 g of the mixture and sealed against moisture to prevent caking.

Instead of poly-((dimethylimino)-ethylene chloride), poly-((2-hydroxyethyl)-methyliminoethylene chloride) or other polymers according to the invention, with varying molecular weights from approx. 1500" to approx.' 50,000 and above, and includes polymers of a single average molecular weight or mixtures of different molecular weights, as long as it is generally above about 1,500.

Hard gelatin capsules

The same dose, i.e. 0.55 g of poly-((dimethylimino)-ethylene chloride) containing 1% by weight of lactose as described above, is filled into the appropriate size hard gelatin capsules.

Alternatively, a dry-filled capsule can be made from the following ingredients:

Dry-filled capsules may likewise be prepared using any of the other novel polymers noted above. If lower strength capsules are produced, the capsule strength may be reduced or additional corn starch or other diluent may be used. When using smaller amounts of active ingredient, it is anticipated that a dose of several capsules can be administered.

Pressed tablets

A dry mixture was prepared from the following ingredients:

4000 tablets were pressed from this batch by direct compression, each tablet containing 250 mg of the ionic polymer. Likewise, pressed tablets are produced so that each tablet contains:

After tableting, a plastic film can be applied to the tablets to seal them against moisture in a manner known per se.

In addition, an enteric coating can be applied, if desired. Such a coating may comprise fat, fatty acids, waxes and mixtures thereof, shellac, ammoniated shellac, and cellulose acid phthalates applied by methods known per se.

Instead of poly-J (dimethyl)-iminoethylene chloride, any of the polymers according to the invention can be used.

Other binders can be used instead of sucrose such as dextrose, lactose, methylcellulose, natural and synthetic gums, and the like. Talc can replace the calcium or magnesium stearate.

A number of readily available non-toxic anti-caking agents can be used in place of the colloidal silicic acid.

Other lubricants, diluents, binders, colorants, flavoring agents and disintegrators can be used as known using wet or dry granulation methods, direct, pressed, spray drying and the like.

If desired, a chewable tablet can be prepared from preferably microencapsulated polymer particles by dry granulation as follows:

The polymers according to the invention are also particularly useful throughout their molecular weight range when they are used as agents for flocculation of colloidal particles in liquids such as e.g. fresh water and sewage water. They can also be used as retention aids when they are added to paper additives during papermaking. Furthermore, the polymers are important as anti-bacterial and anti-static agents and, like the latter, they can be used in the treatment of cotton, wool and synthetic fibres. These polymers can also be used as fabric softeners and dyes, especially to bind the anionic type of dyes. Moreover, they can be used as viscosity builders as well as to increase the bacterial properties of non-ionic and cationic detergent preparations, cosmetics, hair sprays and similar applications. When the polymers according to the invention are used in this way, they are used in an equal amount and in an analogous manner to conventionally known materials that are used for the same purpose.

When they are used as clarifying or flocculating agents, the polymers according to the invention are preferably dissolved or dispersed in an aqueous medium and added to the water to be treated, in an amount of from 60 g to 240 g of polymer per 1000 liters of water to be treated.

In general, the polymers according to the invention have a molecular weight of from 300 to 50,000 or more. Although they are suitable for use as flocculating agents and the like, the polymers having molecular weights below 1500 are not suitable as bile acid binding agents, and such polymer molecules can be separated from the high weight molecules by known methods.

These polymers are administered orally in an effective bile acid binding dose. To lower the blood serum cholesterol level, it is generally a single or multiple dose of from approx. 0.1 to 5.0 g, suitable, although doses above 10 g may be given where necessary. Such doses are also effective in relieving symptoms of pruritus biliary. Administration can take place in a number of forms, such as as a suspension,

in an aqueous solution, as a chewable or coated tablet, or in a capsule, and can be continued for an extended treatment. In general, medication is on a daily basis with each daily dose taken in divided portions, preferably with meals.

To combat hypercholesterolemia, the special individual dose is found, in light of variations in metabolism and diet, by a prior determination and continuous measurement of blood serum cholesterol levels. A moderate dose can thus be used to begin with, and increased until the desired blood serum cholesterol level is achieved and maintained. As an initial dose, which precedes a healthy individual adaptation, from 2.5 to 100 mg/kg body weight per day satisfactory,

A person skilled in the art will recognize that R 1 , R 2 , R 3 and R 3 when they are amino-no-lower-alkyl, lower-alkylammonio-lower-alkyl, di-lower-alkylammonio-lower-alkyl, can also be in the form of the free amine, namely amino-lower-alkyl, lower-alkylamino-lower-alkyl and diloweralkylamino-loweralkyl.

Claims (36)

1. Process for the production of a linear, unbranched, non-crosslinked polymer comprising repeating units of a monomer of the formula: where m is 1 or 0, R' is hydrogen, lower alkyl, phenyl, naphthyl or naphthyl 1, Q is ethylene or trimethylene-, and Z is a counteranion, characterized by a polymer comprising repeating units of a monomer with the formula: where R' and Q are as indicated above, is reacted with at least one molar equivalent of a chemical reducing agent. 2. Method according to claim 1, characterized in that diborane is used as a chemical reducing agent. 3. Process for the production of a linear, unbranched, non-crosslinked polymer comprising repeating units of a monomer of the formula: h.Yor Q is ethylene or trimethylene, and Z is a counteranion, characterized in that a polymer comprises repeating units of a monomer of the formula: where Q is as stated above, is reacted with at least one equivalent of each of formaldehyde and formic acid, and that the resulting mixture is heated at a temperature of 30 - 100° C for up to 100 hours. 4'. Method according to claim 3, characterized in that a mixture of 97 - 100% formic acid and aqueous formaldehyde is used. 5. Process for the production of a linear, unbranched, non-crosslinked polymer comprising repeating units of a monomer of the formula: where Q is ethylene or trimethylene, and Z is a counter anion, characterized in that a polymer comprises repeated units of a monomer with the formula: where Q is as indicated above, is mixed with at least one equivalent of each of formaldehyde and formic acid, and that the resulting mixture is heated. mes to a temperature from 30 to 100° C for up to 100 hours. 6. Method according to claim 5, characterized in that a mixture of 97 - 100% formic acid and aqueous formaldehyde is used. 7. Process according to claim 5, characterized in that Q is ethylene. 8. Process according to claim 5, characterized in that Q is trimethylene. 9. ! Process for preparing a first linear, unbranched, icJce-crosslinked polymer comprising repeating units of a monomer with the formula: where Z is a counteranion, Q is ethylene or trimethylene, m is 0 or 1//vw> indicates attachment to a number of the groups: where Z, Q and m are as above, and R 3 and R 4 , which are the same or different, are lower alkyl; monohydroxy-substituted lower alkyl, polyhydroxy-substituted C 3 to C 8 alkyl or polyhydroxy-substituted C 3 to C 8 cycloalkyl; C3 to C-, cycloalkyl; C3 to C7 cycloalkyl-substituted lower alkyl; lower alkyl-substituted C 3 to C 1 cycloalkyl; ammonium lower alkyl; lower alkylammonio lower alkyl; diloweralkylammonioloweralkyl; trilower alkylammoniolower alkyl; carboxyl-lower alkyl; carbolaverealkylloweralkyl; C3 to C-y alkenyl; C 3 to C 7 alkynyl; aralkyl; carbamylvarealkyl; fluorine lower alkyl1; cyano lower alkyl; .guanidino lower alkyl; carbamidinolaverealkyl; N-lower alkylcarbamidinolower alkyl; lower alkoxy lower alkyl; lower alkylthio lower alkyl; furanosyl; pyranosyl; or lower alkanoyl lower alkyl; characterized in that another polymer comprises repeated monomer units of the formula: where Q is as stated above, is reacted with: (a) when R3 and R^ are equal, at least 1.5 equivalents of RX where R is R3 or R^ and X is halide, sulfate or sulfonate in an inert solvent at a temperature from 30°C to 100°C, and (b) when R 3 and RA are different, the second polymer is first reacted with less than one equivalent of R 3 X in an inert solvent followed by reaction with an amount of a base corresponding to the equivalents of Ranwendt to form a third polymer, then the third polymer is reacted in an inert solvent with a reactant R^X such that the amounts of R^X and R^X used are substantially equivalent to the equivalents of repeating monomer units in the other polymer. 10. Method according to claim 9, characterized in that R 3 and R 1 are methyl, and Q is ethylene. 11. Method according to claim 9, characterized in that Rj and R^ are methyl, and Q is trimethylene. 12. Process for the preparation of a first linear, unbranched, non-crosslinked polymer, comprising repeating units of a monomer of the formula: where X is halide, sulfate or sulfonate, Q is ethylene or trimethylene, and rj\ f\ l indicates attachment to a number of the groups: where X and Q are as above, and R 3 and R 4 , which are the same or different, are lower alkyl; monohydroxy-substituted lower alkyl, polyhydroxy-substituted C 3 to C 8 alkyl or polyhydroxy-substituted C 3 to C 8 cycloalkyl; C 6 to C 7 cycloalkyl; C 3 to C 7 cycloalkyl-substituted lower alkyl; lower alkyl-substituted C3 to C7. cycloalkyl; ammonium lower alkyl; lower alkylammonio lower alkyl; dilaverealalkylammoniolaveraalkyl; trilower alkylammoniolower alkyl; carboxyl lower alkyl; carbolaverealkylloweralkyl; C3 to C7 alkenyl; C3 to C-y alkynyl; aralkyl; carbamylvarealkyl; fluoro-lower alkyl; cyano lower alkyl; carbamidinolaverealkyl; N-lower alkylcarbamidino-lower alkyl; lower alkyl lower alkyl; lower alkylthiolower alkyl; furanosyl; pyranosyl; or lower alkanoyl lower alkyl; and R 1 - and R 2 . which are the same or different are hydrogen, lower alkyl; monohydroxy-substituted lower alkyl, polyhydroxy-substituted C3 to C6 alkyl or polyhydroxy-substituted C- to C8 cycloalkyl; C 3 to C 7 cycloalkyl; C 3 to C 1 cycloalkyl-substituted lower alkyl; lower alkyl substituted C 3 to C 1 cycloalkyl; ammonium lower alkyl, lower alkylammonio lower alkyl; diloweralkylammonioloweralkyl; triloweralkylammonioloweralkyl; carboxyl lower alkyl; carbolaverealkylloweralkyl; C3 to C6 alkenyl; C3 to C? alkynyl; aralkyl; carbamyl lower alkyl; "fluorolower alkyl; cyano lower alkyl; guanidino lower alkyl; carbamidinola lower alkyl; N-lower alkylcarbamidinola lower alkyl; lower alkoxy lower alkyl; lower alkylthio lower alkyl; furanosyl f pyranosyl or lower alkanoyl lower alkyl; characterized by another polymer comprising repeating units of the monomer: where R 3 , R 3 and Q are as indicated above, and /"v/vV indicates binding of a number of the groups: is reacted with <l>(a) , when R^ and R2 are equal, at least one equivalent of RX where R is R-^ and X is halide, sulfate or sulfonate, (b) when R-^ is different from R2, the other is reacted polymer first with 5 - 95% of one equivalent of R-^X, followed by reaction with at least one equivalent of R2X> and then (c) optionally substituting the anion Z for the anion X on the first polymer. 1 13. Method according to claim 12, characterized in that R 1 and R 2 are lower alkyl. 14. Method according to claim 12, characterized in that <R>3 and <R>4 are lower, alkyl. 15. Method, according to claim 12, characterized in that R-^ or R2 is aromonioalkyl 1, lower alkylammonioloweralkyl, diloweralkylammonioloweralkyl or triloweralkylammonioloweralkyl, where the ammonium cation is balanced with an anion Z. 16. Method according to claim 12, characterized in that R-1 or R2 is hydroxy-substituted lower alkyl or hydroxy-. substituted cyclolower alkyl. 17; Process according to claim 12, characterized in that R 1 and <R 4 are methyl. 18. Method according to claim 17, characterized in that Q is ethylene 19. Method according to claim 18, characterized in that the first polymer is poly-({methyl-(2-trimethylammonioethyl)-imino}-ethylene dichloride)-. 20.. Method according to claim 19, characterized in that the first polymer is poly-((dimethylimino)-ethylene ascorbate). 21. Method according to claim 19, characterized in that the first polymer is poly-((dimethylamino)-ethylene-3-trifluoromethylphenoxy-(4-chlorophenyl)-acetate). 22. Process according to claim 17, characterized in that Q is trimethylene. 23. Method according to claim 17, characterized in that the first polymer is poly-({methyl-(3-trimethylammoniopro) pyl)-inino}trimethylene dichloride). 24. Method according to claim 1J, characterized in that the first polymer is poly-((methyl-(3-hydroxypropyl)-imino]-trimethylene chloride). 25. Method according to claim 17, characterized in that the first polymer is poly-({methyl-(3-methoxypropyl)-imino}-trimethylene chloride). 26. Method according to claim 17, characterized in that the first polymer is poly-({methyl-(3-methylthiopropyl)-imino}-trimethylene chloride}. 27. Method according to claim 17, characterized in that the first polymer is poly-({methyl-(2-oxopropyl)-imino}-trimethylene chloride}. 28. Method according to claim 17, characterized in that the first polymer is poly-({methyl-(carboxylatomethyl)-imino}-trimethylene}. 29. Method according to claim 17, characterized in that the first polymer is poly-({methyl-(carbamylmethyl)-imino}-trimethylene chloride}). 30. Method according to claim 12, characterized in that R-1 is methyl. 31. Method according to claim 30, characterized in that R2 is 3-trimethylammoniopropyl halide. 32. Method according to claim 30, characterized in that R 2 is benzyl. 33. Method according to claim 3, characterized in that Q is ethylene. 34. Process according to claim 3, characterized in that Q is trimethylene. 35. Process according to claim 12, characterized in that Q is trimethylene, and R 1 , R 2 , R 3 and R 4 are methyl. 36. Method according to claim 18, characterized in that R-1, R2, R-j and R4 are methyl.