IL44957A - Ionene polymers and methods for their preparation - Google Patents

Description

onaan1? mt>»©i D»e?m o»»aai» a»n»»Via Hovel ionene polymers and methods for their preparation MERCK lb CO. , ©. 42937 Abstract of the Disclosure: Novel polymers having a linear backbone which is free from both branching and cross- linking, comprising either tertiary or quaternized nitrogen atoms linked to each other through ethylene, or trimethylene groups. These polymers are useful as antimicrobials, flocculating agents, antistatic agents, electroconductive agents for coating paper, and chelating agents, bile acid binding agents, as well as in similar applications where their high charge to weight ratio and fully accessible nitrogen atoms can be employed. The polymers are obtained by the polymerization of an oxazoline or dihydro-oxazine, hydrolysis or direct reduction, nitrogen substitution and optional quaternization of that polymer.

Disclosure of the Invention: This invention relates to novel polymers, together with methods for their preparation. More particularly, this invention relates to polymers derived from oxazolines and dihydro-oxazines which have a linear backbone free from both branching and cross- linking, comprising either tertiary or quaternized nitrogen atoms linked to each other through ethylene or trimethylene groups.

These polymers are advantageously employed as anti-microbials, flocculating agents, electroconductive agents in paper coatings, antistatic agents, chelating agents, and bile acid binding agents, as well as in similar applications where their high charge to weight ratio, and the accessi-bility of their nitrogen can advantageously be employed.

They are especially useful as nonabsorbable gastr intestinal bile acid binding agents becatise si.ch binding is known to reduce levels of blood serun cholesterol. All available evidence indicates that the incidence of higher than normal blood serum cholesterol levels in humans (especially in so-called Type II Fredericksor patients) is associated with atherosclerosis and other hypercholesteremia disease signs. Atherosclerosis is manifested hy the effects of occlusion of the circulation, giving rise to coronary, cerebrovascular, and some forms of peripheral vascular diseases and it is the leading cause of death in many countries.

In an effort to reduce the incidence of atherosclero-sis, elevated blood serum cholesterol levels are the target of various control measures, including restricted and special dietary intake, inhibition of cholesterol synthesis, accel-erated catabolism, prevention of gastrointestinal absorption, as well as by means of binding bile acids in the gastrointes-tinal tract. This latter technique is highly favored since it requires neither surgical intervention nor sudden and severe changes in dietary habits or lifestyle of patients.

The exact means by which gastrointestinal bile acid binding accomplishes a lowering of blood serum cholesterol levels is, however, unknown; it is believed feedback mechanisms effect cholesterol oxidation responses depleting serum cholesterol in an effort to restore bile acid levels. Regardless of the uncertainty of its mechaniss". , the technique is well accepted. What is lacking is a convenient, efficient, non-toxic, and easily tolerated binding agent.

Heretofore, a variety of bile acid binding agents have been employed. These include iron salts which produce insoluble precipitates with bile acids, organic bases to act similarly, and polymers having a salt-forr ing capabi-lity. Absorbable precipitants , however, pr sont acute and chronic toxicity hazards. The use of non-absorbable polymers to avoid such toxicity problems has not provided a suitable alternative, because the average effective adult daily dose of such polymers heretofore employed ranges up to 40 grams. The physical bulk of such a dose, especially when of a water-insoluble cross-linked resin, can induce partial blockage of the gastrointestinal tract and an unpleasant, heavy sensation. Furthermore, any objectionable odor and taste of so large a dose is diffi-cult to mask.

Gel-type compositions which have less cross-linking, and are branched, as that term is hereafter defined, swell markedly on water sorption, and although relatively free of abrasive irritation, often cause pressure discomfort.

Water-soluble polymers heretofore proposed for use as bile acid binding agents caiase very high viscosities in solution, and have marked astringent action in the oral cavity. Furthermore, they present much bulk for consumption, retaining as much as an equal weight of water in dry form, Most seriously, they can be degraded in the gastrointestinal tract.

Consequently, there has been only limited benefit derived from treatment by this method, although the incidence of disease linked to hypercholesteremia is extremely high Several explanations are advanced for the inabilitj^^ of resins heretofore suggested for use in hypercholesterol-eraics to match bile acid uptake with the efficiency of chloride capture. One view holds that smaller inorganic anions can easily reach binding sites. Therefore, to make a more efficient resin one should provide greater separation of binding sites for bulky acids. Another view holds that resins need to be more lipid-like to penetrate in vivo micelle formations holding fat-like bile acids, thus leading to suggestions that decreased water solubility for resins was desirable.

Unfortunately, these concepts have produced little improvement when translated into polymer desi n for treating hypercholesterolemia.

We have now found that the novel polymers here-inafter described are exceptionally effective in binding or sequestering bile acids in the gastrointestinal tract, and in lowering blood serum levels of cholesterol.

By the term 1 'salt forming nitrogen' ' is meant a nitrogen atom, e.g., an i ino group or a substituted imino group sufficiently basic that it is either present in the form of a quaternary or an acid addition salt or can form one with acids.

The term ' 'linear polymer backbone ' ' is intended to describe a polymer having only acyclic groups, i.e, methylene or trimethylene groups, linking the nitrogen atoms in a single continuous chain.

The term 1 'unbranched' 1 is intended to mean a polymer having no repeated monomer units extending from That the polymers of this invention are linear and unbranched is of utmost importance in understanding the advances made by this invention. Thus, while some references, e.g., U.S. Patent 3,308,020 disclose monomer units that are similar to the monomer units herein disclosed, it must be remembered that these prior art polymers, by virtue of 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 assert that attempts to polymerize dimethylaminoethylene halides yield only cyclic dimers, notwithstanding the disclosures contained in German Patents 1,131,694 and 1,126,396.

The polymers of this invention are represented J by the wherein R1 and R2 are the same or different and are hydrogen; loweralkyl; monohydroxy-substituted to alkyl, poly-hydroxy-substituted C-j to Cg alkyl and polyhydroxysubstitu-ted C3 to Cg cycloalkyl; C3 to C? cycloalkyl; C3 to C? cyclo-alkyl-substituted loweralkyl; loweralkyl-substituted C3 to C-, cycloalkyl; ammonioloweralkyl; lowaralkylanmoniolower-alkyl; diloweralkylammonioloweralkyl; triloweralkylammonio-loweralkyl; carboxyloweralkyl; carboloweralkoxyloweralkyl; C3 to alkenyl; to alkynyl; aralkyl, e.g., 2(1-naphthyl) ethyl, benzyl; carbamylloweralkyl; fluoroloweralkyl , e.g. , (x)-trifluoroloweralkyl; cyanoloweralkyl; guanidino-loweralkyl; carbamidinoloweralkyl; N-loweralkylcarbamicino-loweralkyl; loweralkoxyloweralkyl; loweralkylthioloweralkyl; furanosyl; pyranosyl, e.g., - ΰ -glucopyranosyl; and loweralkanoylloweralkyl .

R3 and R4. are alike or different and are lower-alkyl; monohydroxy-substituted to alkyl, polyhydroxy-substituted C3 to Cg alkyl and polyhydroxy-s bstituted C3 to Cg cycloalkyl; C3 to C-, cycloalkyl; C3 to C^ cycloalkyl-substituted loweralkyl; loweralkyl-substituted C3 to C^ cycloalkyl; ammonioloweralkyl; loweralkylammonioloweralkyl; diloweralkylammonioloweralkyl, triloweralkylarcmoniolower-alkyl; carboxyloweralkyl; carboloweralkoxyloweralkyl; C3 to C7 alkenyl; C3 to alkynyl; aralkyl, e.g., 2(1-naphthyl) ethyl , benzyl; carbamyloweralkyl ; fluorolower-alkyl, e.g., GJ-trifluoroloweralkyl; cyanoloweralkyl ; guanidinoloweralkyl; carbartiidinoloweralkyl; N-loweralkyl-carbartiidinoloweralkyl; loweralkoxyloweralkyl; loweralkyl-thioloweralkyl; furanosyl; pyranosyl, e.g, α- -gluco-pyranosyl; and loweralkanoylloweralkyl. n is an integer such that the wei^h- average molecular weight is from 300-50,000; m is 0 or 1; Z is a monovalent or polyvalent counter anion; Q is ethylene or trimethylene ; and the symbol A/l\ indicates a bond to a plurality of the groups R- R, where Q, Z, m, R^, R2 , R3 and R4 have their previously de-fined meanings.

T, and T~ are terminal groups on the polymer and 2 or a dihydro-1 ,3-oxazinium or a Δ -oxazoliniun complex with previous meanings, R,. is selected from the same group as R^ and , but may be the same or different from either one or both of R^ and ^ , and R* is a fragment derived from a solvent wherein the ring opening was effected, e.g., hydrogen if an aqueous treatment was employed, or an alkyl if an alcohol treatment was employed. The exact nature or identity of T is actually immaterial to the invention, or the utility of the polymers hereinafter described.

The prefix 1 ' lower 1 ' as used herein indicates from 1 to 4 carbon eJtoras, and as the other above-referred to alkyl groups, can be a straight chain.

In the above, if m is 1, Q is trimethylene , and ^, R^' 2 and R^ are loweralkyl, the compounds thus described are known. Yet, the methods disclosed herein to prepare these compounds are novel.

In a preferred embodiment, the polymer has the structure where t t Z L indicates bonding to one or more groups Z, T^, 2, Q, m and n have their previously defined meanings.

In another preferred embodiment, the polymer has the structure indicated in formula III below: Ill v- 1 where η/Ι Ι indicates bonding to one or more groups ( flZ+)m (f2Z+)m — N Q — or — — Q— , and R. , R_ I I Cii3 CH3 2 Z , T^ , T2 , Q , m and n have their previously defined 3 meanings. 4 Throughout this description, Z represents an anion 5 which counters the charge on the quaternized or protonated 6 imino group, and thus can be a monovalent anion. It is to 7 be understood, however, that Z is contemplated to include 8 polyvalent anions where one anion can counter the charge on 9 more than one charged imino group. Thus, Z can include 10 anions of inorganic acids, as well as from organic acids 11 such as, for example, halide, e.g., chloride, bromide, or 12 iodide; sulfate; bisulfate; phosphate; acetate; ascorbate; 13 citrate; hydroxycitrate; carbonate; bicarbonate; nicotinate; 14 glycinate; taurinate; salicylate; and other anions derived 15 from physiologically non-toxic acids, especially salts of 16 physiologically active acids such as those derived from 17 clofibrate and halofenate, i.e., 2- (p-chlorophenoxy) -2- 18 methylpropionic and 3-trifluoromethylphenoxy- (4-chlorophenyl) 19 acetic acids. When such anions of physiologically active 20 compounds are used to neutralize quaternized or protonated 21 imino groups, it is apparent that only a portion of the 22 charged imino groups may be so neutralized. The amount of 23 anion from the physiologically active compound is apportioned 24 in a ratio such that the amount administered with the polymer 25 dosage can fall within the desired range for the physiologi- 26 cally active compound. a -dihydro- -oxazine of the formula: where R* is hydrogen, loweralkyl, phenyl, naphthyl, or naphthylmethyl . Preferably, R* is hydrogen.

STEP - Polymerization The polymerization of the -R'-A -oxazolines is known and is reported in Polymer Journal, We have found, however, that a more reliable polymerization is obtained by using trifluoromethylsulfonic acid in place of the initiators reported in the literature. Generally, from to moles of trifluoromethylsulfonic acid is used for each mole of a -R'-A -oxazoline, with mole of the trifluoromethylsulfonic acid par mole of -R'-i -oxazoline being preferred.

The polymerization of the -R -dihydro -l oxazine is also known and is reported in Macromolecules , . The preferred initiator of the known initiators is methyl iodide.

Generally, the polymerization of the -R'--\ -oxazolines and the -R -dihydro -l -oxazines is carried out in a closed system in an inert solvent and under an inert atmosphere such as nitrogen at a pressure of from atmospheres and heating to from to for a period of from hours. By inert solvent, either with reactants, products or itself, dinethylformamide here being the preferred solvent.

After reaction is deemed complete, as determined by the disappearance of the -C=N- double bond, the polymerization reaction mixture, now comprising the polymer VI where R' , Q and n are as previously defined and 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* are as previously defined, is treated with an anhydrous solvent preferably an alcohol or ether such as methanol or ethyl ether. After filtration and washing with anhydrous solvent, the polymer is collected and dried.

After isolation, the polymer is next subjected to either one of three alternative second steps: 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 VII VII where A, m, Q , Z, R*, and n have their previous mean ings, and Z is preferably a halide.

The alkaline hydrolysis is accomplished by admixing the polymer with an aqueous solution of from saturated to 0.1N base, suitably alkali hydroxide and preferably sodium hydroxide. The acid hydrolysis is carried out in 1 to 2 aqueous mineral acid, e.g., HC1 or I^SO^.

The hydrolysis is conducted with agitation and warming for at least 3 to 30 hours. Preferably, to achieve substantially complete hydrolysis at a slight sacrifice in molecular weight, the hydrolysis can be carried out in a sealed vessel at a temperature of from 40°C. to 180°C. The quantity of aqueous hydrolyzing solution is not critical, provided that agitation is good and at least twice the theoretical amount of alkali or acid is employed to effect the hydrolysis.

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

STEP 2B - Direct Reduction Polymer VI is reduced directly to polymer VIII by reduction of the jacyl group. where A, , Q, R' , R* , Z , m and n are as previously defined.

Preferably, the polymer is dissolved in an inert solvent and slowly admixed with at least a molar equivalent of a chemical reductant such as diborane which also is dissolved in an inert solvent. The preferred solvents are tetrahydrofuran and mixtures thereof with ethyleneglycol dimethyl ether. After addition, the reaction mixture is refluxed for 1-12 hours, cooled and acidified. Other reducing agents which can be employed in place of the diborane include aluminum .hydride , lithium aluminum hydride, and lithium tri-methoxy aluminum hydride.

Alternatively, the amide groups of polymer VI are converted by alkylation to imino esters with triethyloxonium tetrafluoroborate complex in methylene chloride at 25°C.

The imino ester moieties are then readily reduced to tertiary amine moieties as with sodium borohydride in ethanol at 0°C. to 25°C.

STEP 2C - Reductive Methylation In this procedure polymer VI where R' is hydrogen is heated with a mixture of more than one equivalent each of formaldehyde and formic acid, then treated with an aqueous acid and concentrated to dryness under reduced pressure where R^, , Z, R* , m and n have their previous meanings.

The polymer to be reductively methylated is added to a mixture of 97% to 100% formic acid and preferably 38% a temperature of from 30 °C. to 100 °C. for a period of from ^ 20 to 100 hours. Although higher reaction temperatures are not prohibited, the increased rate of thermal decompo-sition 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 formic acid, formaldehyde and mineral acid are removed by concentration under reduced pressure.

STEP 3 - Direct Methylation Polymer VII where m is 0 is methylated directly by heating the polymer in a mixture of more than one equiva-lent each of formaldehyde and formic acid under conditions described in Step 2C to yield polymer IX where R,., Q, Z, R* , m and n have their previous meanings.

STEP 4 - Addition of and R¾ to Polymer VII For polymers of formula X in which R^ and R^ are the same, polymer VII where m is 0 is treated with an excess ranging from 1.5-8 equivalents, and preferably 4 equivalents, of an alkylating agent RX in an inert solvent at tempera-tures ranging from 30°C. to 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 pre-ferred temperatures are between 50 °C. to 75 °C. This results in a polymer of formula X in which A, Q, Z, R* and n have their previous meanings and m is 1 and Z is X . Treat-ment of polymer X with exactly one equivalent of base yields polymer X in which m is 0. than an equivalent amount of an alkylating agent R-jX and then after neutralization with a matching equivalent of base the intermediate is treated with sufficient R4X to complete alkylation. Both reactions are conducted in an inert solvent at temperatures ranging from 30 °C. to 100°C. The reactions are conducted by dissolving the polymer in an inert solvent such as alcohols, ketones or dimethylfor-mamide. Preferred solvents include methanol, acetone and dimethylformamide , and preferred temperatures are between 50°C. to 75 °C. Acid neutralization forms polymer X in which A, Q, Z, R* and n have their previous meanings and m is 1, and Z is X . Treatment of polymer X with exactly one equivalent of base yields polymer X in which m is 0.

Polymer VIII, from Step 2B, polymer IX, from Step 2C or Step 3, or polymer X, from Step 4, usually obtained as their acid addition salts (m=l) , are converted to the free base form (m=0) on treatment with an equivalent amount of base. At this stage, it is convenient, though not necessary to remove any inorganic salts by ultrafiltra-tion techniques. This has the added advantage of also eliminating any other undesirable lower molecular weight material. The aqueous solution of the polymer is then concentrated under reduced pressure and the product is dried prior to the quaternization reaction that leads to polymers of formula I. The quaternization reaction is accomplished 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 bromo compounds; other alkylating agents such as toluenesulfonate esters or trichloromethylsulfonate esters can also be eraployed. When and are the same, a reasonable excess of the alkylating agent RX is employed; when and R2 are different, the polymer is first treated with a limiting amount (5% to 95% of equivalence) of R^ . After that reaction is complete, the product is treated with an excess of reagent R2X* When tne alkylating reactivities of the reagent R1X and R,,X are the same, the reaction may be carried out in a mixture of R^X and R2X in a single step. The R^X and R2 may be simple alkyl halides or may also carry other functional groups which do not interfere with the quaternization reaction. A simple but by no means exhaustive list of acceptable quaternization reagents includes haloalkyl acid esters, haloalkyl acid amides, haloketones, fluoroalkyltrichloromethylsulfonates , alkyl halohydrins, aralkyl halides, ammonioalkyl halides, loweralkyl-substituted ammonioalkyl halides, alkoxyalkyl halides, alkylthioalkyl halides, allyl halides, and propar-gyl bromide* The reaction is usually carried out by heating a solution of the polymer and alkylating agent in methanol, acetone or dimethylformamide at 35°C. to 100°C. for three to sixteen hours. With particularly reactive alkylating agents, a reaction temperature of 50 °C. is employed. The product is usually isolated directly by filtration, but in some instances it is expedient to dilute the reaction mixture with several volumes of ether prior to filtration. The product is usually partially dried, ground to a powder and then dried under reduced pressure at temperatures of from 25°C. to 60°C.

STEP 6 - Ion Exchange The anions on polymer I are generally limited to halide by the techniques of the prior steps. The full range of polymers where the anion Z differs from halide can be obtained by dissolving polymer I having a halide anion in water, alcohol, or mixtures thereof in any proportion and passing the solution through a bed 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 em-ploying a resin technique can be direct, that is, exchanging halide ion for Z or one can first exchange halide ion for OH and then either by a subsequent ion exchange or simple neutralization exchange OH~ for Z~.

Additionally, chemical exchange techniques can be employed when a precipitate 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 technique involves treating a solution of polymer I containing the bromide counter ion 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 counter ion. Alternatively, polymer I where Z is sulfate can be treated wi h solutions of watei: soluble cal- EXAMPLE I ^ Poly-[ (Formimino) ethylene] 2 A solution of 44 g. of Δ -oxazoline and 870 mg. of freshly distilled boron trifluoride etherate in 175 ml. of purified dimethylformamide is placed in a pressure reactor containing a glass liner and the system is purged with nitrogen. The mixture is heated at 80 °C. for five hours and then diluted with methanol and filtered yielding 30 g. of the poly- [ (formimino) ethylene] polymer. In a five-hour reaction period at 80°C. and boron trifluoride etherate 2 catalyst at 0.01 mole ratio to that of Δ -oxazoline, the yield of solid polymer ranges from 13.2% to at least 68%.

EXAMPLE II Poly-[ (Formimino) ethylene] A solution of 217 g. (3.06 moles) of Δ -oxazoline and 4.6 g. (0.03 moles) of trifluoromethylsulfonic acid in 800 ml. of purified dimethylformamide in a sealed tube and under a nitrogen atmosphere is heated at 90°C. and agitated for five hours. After being cooled, the mixture is diluted with 1200 ml. of anhydrous methanol and the product is iso-lated by filtration. The product is washed with methanol and then ether prior to being dried under reduced pressure. This reaction yields 150 g. of poly-[ (formimino) ethylene] .

EXAMPLE III Poly- [ (Acetimino) ethylene ] A 1 g. sample of 2-methyl-A -oxazoline is charged into a Carius combustion tube with two drops of boron trifluoride etherate (48%) . The tube is thoroughly flushed polymer is a glassy, nearly colorless resin with a melting range of 155°C .-175°C . The polymer is readily soluble in methylene chloride.

EXAMPLE IV Poly-[ (Butyrimino) ethylene] In this example, an N-acylethyleneirnine is poly-merized using a single catalyst system which also causes rearrangement to an intermediate oxazoline.

N-Butyrylethyleneimine , 10 cc. , and BF^ «EtO , 0.05 cc. , in an evacuated tube is heated at 60°C. for four hours. The resulting solid is dissolved in 100 ml. CIIC13, precipi-tated by the addition of petroleum ether, redissolved in CHCl^ and reprecipitated by petroleum ether. The precipitate is dried yielding 6.3 g. of poly-[ (butyrimino) ethylene ] having a reduced viscosity of 0.16 in a 1% solution in benzene, and m.p. 150°C.

In an analogous manner but employing: N-benzoylethyleneimine 2 2-isopropyl-A -oxazoline 2 2-cyclohexyl-A -oxazoline 2 2-naphthyl-A -oxazoline 2 2-p_-tolyl-A- -oxazoline there is obtained the corresponding poly- [ (benzoylimino) ethylene] poly-[ (isobutyrimino) ethylene] poly-[ (cyclohexanoylimino) ethylene] poly-[ (naphthoylimino) ethylene] poly-[ (toluoylimino) ethylene ] EXAMPLE V Poly- [ (Benzoylimino).ethylene] 2-Phenyl-2-oxazoline (1.1322 g., 7.Γ0 x 10~3 mole) is charged into a Carius combustion tube with 7.69 -5 x 10 mole of boron trifluoride xn the form of a dimethoxy-ethane solution. After evacuation, flushing v/ith nitrogen and sealing, the sample is heated at 150 °C. for two hours. One gram of the resulting light yellow glassy polymer is ground to a fine powder and dissolved in 25 ml. of methylene chloride. This solution is added to 75 ml. of n-hexane that is being stirred vigorously to give a thick, white precipi-tate. The material is filtered and reprecipitated two more times in the same manner to yield a fine, white powder. The recovery of purified poly- [ (benzoylimino) ethylene] polymer is 80%. The molecular weight of this polymer is 7500.

EXAMPLE VI Copolymerization of Equimolar Mixtures of 2-Phenyl-2-oxazoline and Other 2-Substituted-2-oxazolines Equimolar monomer concentrations of 2-phenyl-2-oxazoline and respectively 2-benzyl-2-oxazoline; 2-methyl-2-oxazoline; and 2-isopropyl-2-oxazoline at concentrations of 1.5 mole/liter in Ν,Ν-dimethylacetamide are each heated at 135 °C. for approximately two hours using 2-phenyl-2-oxazolinium perchlorate as an initiator. The resultant poly- [ (acylimino) ethylene] copolymers vary randomly as to content of N-acyl groups. The 2-pheny1-2-oxazoline gives rise to the N-benzoyl derivative; the 2-benzyl-2-oxazoline forms the N-phenylacetyl derivative and the 2-methyl analog forms the N-acetyl derivative. The composition of the copolymer regarding the degree of randomness is influenced by the relative reaction rates of the various monomers. Since the resulting polymers may be for produc-tion of linear poly- (ethyleneimine) , the different acyl group composition is without significance because acyl groups are removed by hydrolysis. They can, of course, be reduced directly as described in a subsequent example .

EXAMPLE VII Poly- (Iminoethylene) The hydrolysis of a poly- [ (acylimino) ethylene] is accomplished by acid or base hydrolysis. (a) Illustrating 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 three hours. The solution is cooled to room temperature and the white solid which precipitates is isolated by filtration, washed thoroughly with water and dried in vacuo , yielding 1.6 g. of poly- (iminoethylene) . (b) A 1.29 g. sample of poly-f (acetimino) ethylene] is added to 50 ml. of approximately IN sodiur. hydroxide.

The polymer is virtually insoluble in base at room temper-ature; however, after being refluxed 26 hours the reaction mixture becomes homogeneous. Cooling to room temperature causes the reaction mixture to gel to a white mass.

Hydrolysis is approximately 65% complete. The non-acylated poly- (iminoethylene) is purified by repeated precipitation, i.e., solution into acid, filtration from partially acety-lated poly- (iminoethylene) and neutralization of the filtrate. mixture results which is heated under reflux for 3.5 hours, the odor of acetic acid becoming apparent. After this time, the titration of an aliquot portion with IN sodium hydroxide indicates a 27% completion of hydrolysis. After 21 hours at reflux, hydrolysis is 38% complete.

Generally, a substantially complete hydrolysis is obtained by conducting the hydrolysis as above, but in a sealed tube at 120°C, or higher temperatures.

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

EXAMPLE VIII Poly-[ (Ethylimino) ethylene] To a solution of 200 ml. (334 mmole) of 1.67 diborane in tetrahydrofuran in a 500 ml. flask equipped with a reflux condenser, dropping funnel, magnetic stirring bar, and maintained under nitrogen is added 17 g. (200 mmole/monomer unit) of poly- [ (acetimino) ethylene ] in 100 ml. of tetrahydrofuran over 15 minutes. The temperature is maintained at approximately 0°C. during the addition.

The reaction mixture is then maintained at reflux for six hours. The mixture is permitted 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 mole) from the hydrolysis of the amine-borane complex. Sodium hydroxile is added to In an analogous manner each of the polymers ^ obtained in Example IV are reacted to form respectively: poly-[ (benzylimino) ethylene ] ; poly- [ (isobutylimino) ethylene ] ; poly-[ (naphthylmethylimino) ethylene] .

EXAMPLE IX Poly-[ (Methylimino) ethylene Hydrochloride] Two and five-tenths grams of poly- (iminoethylene) is added slowly to 12 g. of 90% formic acid and 5.5 g. of 38% aqueous formaldehyde is added. After the mixture is heated at 100°C. for 72 hours, it is cooled, and 5.5 ml. of concentrated HCl is added. The mixture is concentrated to dryness under reduced pressure, yielding 5 g. of poly-[ (methylimino) ethylene hydrochloride].

EXAMPLE X Poly-[ (Dimethylimino) ethylene Chloride] Five hundred milligrams (5.4 mmoles) of poly-[ (methylimino) ethylene hydrochloride] is dissolved in 50 ml. of methanol containing 291 mg. (5.4 mmoles) of sodium methoxide. The solution is cooled in an acetone-dry ice bath, and 10 g. of methyl chloride is condensed into the solution. This mixture is heated in a sealed tube at 80°C. for five hours. This mixture is concentrated to dryness under reduced pressure and the product is taken up in 3 ml. of anhydrous methanol and filtered and the solution is con-centrated to dryness. Dissolution of the product in methanol, filtration, and then concentration to dryness is repeated several times. The filtrate is concentrated under reduced pressure yielding 400 mg. of poly- [ (dimethylimino) - EXAMPLE XI Poly-[ (Dimethylimino) ethylene Bromide] A solution of 860 mg. (20 milliequiv.) of poly-(iminoeth lene) in 30 ml. of methanol is treated with 9.5 g. (100 mmoles) of methyl bromide at 50 °C. for three hours.

The reaction mixture is concentrated to dryness under re-duced pressure. The residue is treated with 1.08 g. (20 mmoles) of sodium methoxide in 10 ml. of methanol and con-centrated to dryness. The residue is taken up in 30 ml. of anhydrous methanol and treated with 9.5 g. (100 mmoles) of methyl bromide; the solution is heated at 50 CC. for three hours. After concentration, the product is taken up in water, and the solution is subjected to ultrafiltration through a VM 2 Diaflo Ultrafilter. The retentate is then concentrated under reduced pressure yielding 2.8 g. of poly- [ (dimethylimino) ethylene bromide].

EXAMPLE XII Poly-[ (Dimethylimino) ethylene Methosulfate] 0.5 Gm. of poly-[ (methylimino) ethylene hydrochloride] is dissolved in 50 ml. of methanol containing 0.29 gm. of sodium methoxide. The solution is concentrated to about 20 ml. and 0.7 gm. of dimethyl sulfate is added. The solution is then heated 6 hours at 50°C, and the product is precipi-tated by pouring the solution into a large volume of acetone or by evaporation of the methanol followed by acetone wash. The product is dried at ambient temperature under reduced pressure.

EXAMPLE XIII Poly- [^(2-Hydroxyethyl) methylimino^ ethylene Chloride] The procedure of Example X is followed, but there 10 g. of methyl chloride. The mixture is heated at 80 °C. for five to seven hours and then freed of solvents and excess reagents by stripping under reduced pressure. The residue is poly-[^(2-hydroxyethyl)methylimino - ethylene chloride ] .

In an analogous manner an equivalent amount of propylene chlorohydrin or sec-propylene chlorohydrin is respectively substituted for the ethylene chlorohydrin giving poly-[^(l-methyl-2-hydroxyethyl)methylimino^' ethylene chloride] and poly-[^(2-hydroxypropyl) methylirdno - ethylene chloride].

EXAMPLE XIV Poly-[(2-Hydroxyethylimino) ethylene ] 0.5 Grams of the poly- (iminoethylene) of Example VII is dissolved in 50 ml. of methanol and heated with 0.35 g. ethylene oxide in a sealed tube under nitrogen at 60°C. for three hours. The solvent and excess epoxide are removed by stripping under reduced pressure. The residue is poly- [ (2-hydroxyethylimino) ethylene ] .

EXAMPLE XV Poly- [^(2-Hydroxybutyl) -2-hydroxyethylimino^ ethylene Bromide] The poly- [ (2-hydroxyethylimino) ethylene] from the previous example is heated in 50 ml. of acetone with 20 g. of 2-hydroxybutyl bromide at 80°C. to 90°C. in a sealed tube for six to eight hours.

The product is recovered as before by removal of solvent and excess reagent under reduced pressure. The residue is poly- [-£(2-hydroxybutyl) -2-hydroxyethylimino--eth lene bromide .

EXAMPLE XVI Poly-[ (Methylimino) ethylene Hydrochloride 3 A mixture of 25 g. of poly- (formiminoethylene) , 504 g. of 97%-100% formic acid and 118 g. of 38% aqueous formaldehyde (formalin) is heated at 100 °C. for 60 hours.

The reaction mixture is cooled, 210 ml. of concentrated hydrochloric acid is added, and the mixture is concentrated to dryness under reduced pressure at 50 °C. After the product is washed with methanol, then ether and dried, 34.6 g. of poly- [ (methylimino) ethylene hydrochloride] is obtained.

EXAMPLE XVII Poly-[ (Methylimino) ethylene] A solution containing 0.325 mole of sodium hydroxide is prepared by dissolving 17.55 g. of sodium nethoxide in 400 ml. of water. To this is added 28.6 g. (0.31 mole) of poly- [ (methylimino) ethylene hydrochloride], and the total volume of the solution is made up to 500 ml. by the addition of water. The solution is then desalted and also rid of any product with a molecular weight of less than 1000 using an Amicon filter cell equipped with a UM2 Diaflo Ultrafilter. Next, the solution is concentrated under reduced pressure at 50°C. yielding 16 g. of poly- [ (methylimino) ethylene] .

EXAMPLE XVIII Poly-[ (Dimethylimino) ethylene Bromide] A solution of 21.7 g. (0.38 mole) of poly-[ (methyl-imino) ethylene ] in 130 ml. of anhydrous methanol is cooled and 364 g. (3.8 moles) of condensed methyl bromide is added. The mixture in a glass-lined pressure reactor is heated at 50 °C. for five hours. After the mixture is cooled, the product is isolated by filtration, washed with ether and dried under reduced pressure to give 58 g. of poly- [ (dimethylimino) ethylene bromide].

EXAMPLE XIX Poly-[ (Dimethylimino) ethylene Chloride] A solution of 58 g. of poly- [ (dimethylimino) -ethylene bromide] (0.38 mole) in three liters of water is passed slowly (10 ml./min.) through a 770 ml. column of 200-400 mesh AG1-X8 quaternary ammonium chloride resin (1078 milliequivalents of Cl~) . After 4200 ml. of effluent is collected, it is concentrated under reduced pressure at 50°C.-55°C. and dried to give 37 g. of poly- [ (dimethy1-imino) ethylene chloride ] .

EXAMPLE XX Preparation of Poly- [ (dimethylimino) ethylene Ascorbate] 5.0 Grams of poly- [ (dimethylimino) ethylene chloride] is dissolved in 75 ml. of distilled water and passed down a column containing 100 gms. (0.5 mole Cl~ exchange capacity) of a polystyrene resin, the benzene ring of which is substituted with 4-methotrimethyl ammonium hydroxide (Bio Rad AG 1 x 8) . Six column volumes of the eluate (450 ml.) containing poly- [ (dimethylimino) ethylene hydroxide] is collected, concentrated to 150 ml., cooled to 15°C, and neutralized with 8.8 gms. (0.05 moles) of ascorbic acid, U.S.P. The clear neutralized solution is then shell frozen and lyophilized to give a white solid which is readily pulverized.

The other polymers of this invention can like-wise be transformed to the ascorbate salt, or by employing other acids containing physiologically acceptable anions in place of the ascorbic acid, there can be obtained the other salts theretofore described.

EXAMPLE XXI 5 , 6-Dihydro-4H-l , 3-oxazine A mixture of 94 g. (1.13 moles) of t-butyl iso-nitrile, 85 g. (1.13 moles) of freshly distilled 3-amino-propanol, and 7.4 g. (0.055 mole) of silver cyanide is stirred at 90°C. under a nitrogen blanket for 16 hours. The product is isolated from the reaction mixture by distillation at 45 mm. and is purified by repeated fractionation. Usually, two such fractionations suffice to yield a pure product. In this manner, 44 g. of pure 5, 6-dihydro-4H-l, 3-oxazine, b.p. 25 58°C./ 58 mm., ηβ 1.4485 is obtained and stored over molecular sieves type 4A and under nitrogen.

EXAMPLE XXII Poly-[ (Formimino) trimethylene ] A solution of 44 g. (0.52 mole) of 5 ,6-dihydro-4H-1, 3-oxazine in 140 ml. of purified dimethylformamide is put in a pressure tube and 1.52 g. (0.011 mole) of iodomethane is added. The system is purged with nitrogen, sealed and heated at 80°C. for five 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. yielding 40 g. of poly- [ (formimino) trimethylene , m.p. decomposes at 111°C.-112°C.

EXAMPLE XXIII ' Poly-[ (Methylimino) trimethylene Hydrochloride] A mixture of 53 g. of poly- (formiminotrimethylene) , 1320 g. of 97%-100% formic acid, and 308 g. of 38% aqueous formaldehyde is heated at 100°C. for 120 hours. After the solution is cooled, 650 ml. of concentrated hydrochloric acid is added, and the mixture is concentrated 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 yielding 67 g. of poly-[ (methylimino) trimethylene hydrochloride].

EXAMPLE XXIV Poly-[ (Methylimino) trimethylene] A solution of 67 g. (630 milliequiv.) of poly-[ (methylimino) trimethylene hydrochloride] in 600 ml. of water is treated with 39 g. (0.72 mole) of sodium methoxide. This is simply an easy way to prepare a solution of sodium hydro-xide of precise normality. A corresponding volume of a standardized solution of sodium hydroxide is equally adequate. The solution is desalted and polymer with molecular weight below 1,000 is removed using an A icon filter cell equipped with a UM2 Diaflo Ultrafilter. Finally, the solution is concentrated at 50 °C. under reduced pressure yielding 45 g. of poly- [ (methylimino) trimethylene] .

EXAMPLE XXV Poly-[ (Dimethylimino) trimethylene Broraide] A solution of 14 g. (200 milliequiv.) of poly-[ (methylimino) trimethylene] and 76 g. (0.8 moles) of bromo-methane in 90 ml. of methanol is heated at 50 °C. in a sealed reactor for five hours. The product is isolated by filtra- EXAMPLE XXVI Poly-[ (Dimethylimi.no) trimethylene Chloride] A solution of 28 g. (170 milliequiv.) of poly- [ (dimethylimino) trimethylene bromide] in 1400 ml. of water is passed slowly through a column containing 1,000 ml. of Dowex 1-X2 (Cl cycle) resin (0.8 mole) . After the solution has passed through, water is passed through the column until a negative silver nitrate test is observed with the effluent. The total effluent is concentrated to dryness, and the product is dried under reduced pressure yielding 17.2 g. of poly- [ (dimethylimino) trimethylene chloride].

EXAMPLE XXVII Poly- [-^Methyl- ( 3-hydroxypropyl) imino^trimethylene Bromide ] A solution of 142 mg. (2 milliequiv.) of poly-[ (methylimino)trimethylene ] and 1.12 g. (8 mmoles) of 3-bromo- propanol 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 yielding 330 mg. of poly-E^methyl- (3-hydroxypropyl) iminq}-trimethylene bromide].

EXAMPLE XXVIII Poly- ^(Methyl- (3-hydroxypropyl) imino^trimethylene Chloride A solution of 315 mg. (1.5 milliequiv.) of poly- [-^methyl- (3-hydroxypropyl) imino^trimethylene bromide] in 16 ml. of water is passed slowly through a column of 9 ml. of Dowex 1-X2 ion exchange resin (7.2 mmoles chloride ion) , and then water is passed through until the effluent gives a negative test for chloride ion. The combined effluent ° yielding 230 mg. of poly- [^methyl- ( 3-hydroxypropyl) imino trimethylene chloride ] .

In the preceding example, a polymer of Formula III is synthesized in which R^ and are each 3-hydroxy- propyl. The following three examples will demonstrate how polymers of Formula III can be synthesized with R^= 3- hydroxypropyl and I^CH^. In these examples the and R constitute from 5-95% and 95%-5% respectively of the sum of R^ + R2 and are distributed randomly along the polymer backbone .

EXAMPLE XXIX Polymer of Formula III in which R.= 3-hydroxypropyl and R_= CH^ (Randomly distributed in a 5; 95 ratio) A solution of 462 mg. (6 milliequiv.) of poly-[ (methylimino)trimethylene] and 41 mg. (300^moles) of 3-bromo- propanol in 12 ml. of dimethylformamide is heated at 75°C. for 24 hours. The mixture is cooled and 2.9 g. (30 mmoles) of methyl bromide is added. The reaction mixture is heated at 50°C. for three hours. The product is isolated by con- centration of the reaction mixture under reduced pressure and is washed with ether and dried under reduced pressure. Exchange of the bromide counter ion by chloride ion is accomplished in the usual manner employing an ion-exchange resin as described above.

EXAMPLE XXX Polymer of Formula III in which R. = 3-hydroxypropyl and R2 = CH3 (Randomly distributed in a 50T50 ratio) A solution of 213 mg. (3 milliequiv.) of poly-[ (methylimino)trimethylene ] and 209 mg. (1.5 mmoles) of 3-bromo- propanol is heated at 75 °C. for 24 hours. The reaction mix- i: EXAMPLE XXXI Polymer of Formula III in which R, = 3-hydroxy ropyl and = CH3 (Randomly distributed in a 95:5 ratio) A solution of 142 mg. (2 miiliequiv.) of poly-[ (methylimino)trimethylene ] and 264 mg. (1.9 mmoles) of 3- bromopropanol is heated at 75°C. for 16 hours. After the mixture is cooled, 1 g. of methyl bromide is added and the mixture is heated at 50 °C. for twelve hours. The reaction mixture is worked up in the manner described above.

. EXAMPLE XXXII Poly- [.^Methyl- (3-methoxypropyl) imino^trimethylene Chloride ] A solution of 284 mg. (4 miiliequiv.) of poly-[ (methylimino)trimethylene ] and 2.45 g. (16 mmoles) of 3- methoxypropyl bromide in 15 ml. of dimethylformamide is heated at 75 °C. for sixteen 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 counter ion is exchanged for chloride ion by ion-exchange as described above. In this manner, 450 mg. of poly-Dimethyl- (3-methoxypropyl) imino^ trimethylene chloride] is obtained.

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

EXAMPLE XXXIII JL Poly- [^Methyl- (3-methylthiopropyl) imino trimethylene Chloride ] A solution of 426 mg. (6 milliequiv.) of poly-[ (methylimino)trimethylene] and 4.06 g. of 3-methylthiopropyl bromide 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 of 45 ml. of Dowex 1-X2 ion-exchange resin (36 mmoles chloride ion) . Concentration of the aqueous eluate yields 650 mg. of poly- [·£methyl- (3-methylthiopropyl) imino^trimethylene chloride].

For the synthesis of polymers of Formula III in which and are 3-methylthiopropyl and methyl respectively in ratios varying from 5:95 to 95:5, the procedure is essen- tially as described above in which the poly- [ (methylimino) tri- methylene] is reacted with a limiting amount of 3-methylthio- propyl bromide and then with an excess of methyl bromide.

EXAMPLE XXXIV Poly-[^Methyl- ( 3-ammoniopropyl) imind^-trimethylene Dichloride ] A solution of 568 mg. (8 milliequiv.) of poly- [ (methylimino)trimethylene] and 8.6 g. (30 mmoles) of 3-phthal- imidopropyl bromide in 25 ml. of dimethylformamide is heated at 75 °C. for eighteen 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 three hours. The mixture is concentrated at reduced pressure, acidified with dilute HCl, triturated with ether and isolated by filtration. The product is taken up in water and passed through a 45 ml. column of Dowex 1-X2 ion-exchange resin (36 mmoles chloride ion) . Concentration of the aqueous eluate yields poly-[- methy1- (3-ammoniopropyl) imino^tri- methylene dichloride].

Alternatively, a solution of 568 mg. (8 milli- equiv.) of poly-t (methylimino)trimethylene ] and 6.3 g. (40 mmoles) of l-bromo-3-chloropropane in 20 ml. of dimethyl- formamide is heated at 75°C. for eighteen hours. The reac- tion mixture is concentrated under reduced pressure and heated with 30 ml. of liquid ammonia at 50°C. for five hours. The ammonia is allowed to evaporate, and the product is con- verted to the chloride-ion containing form by passage through a 45 ml. column of Dowex 1-X2 ion-exchange resin on the chloride ion cycle.

For the synthesis of polymers of Formula III in which and are 3-ammoniopropyl and methyl respectively in ratios varying from 5:95 to 95:5, the procedure is essentially as described above in which the poly-i ( ethyl- imino)trimethylene] is reacted with a limiting amount of either 3-phthalimidopropyl bromide or l-bromo-3-chloropro- pane and then with an excess of methyl bromide.

EXAMPLE XXXV Poly- [-^Methyl- (3-methylammoniopropyl) imino)-trimethylene Dichloride] A solution of 710 mg. (10 milliequiv.) of poly-[ (methylimino)trimethylene ] and 8 g. of l-bromo-3-chloropropane in 30 ml. of dimethylformamide is heated at 75°C. for 16 hours. The mixture is concentrated under reduced pressure, suspended in 10 ml. of methanol and treated with 3 g. of methylamine at 50 °C. in a sealed tube. The reaction mixture is concentrated under reduced pressure, taken up in water and passed through a 50 ml. column of Dowex 1-X2 ion exchange resin to yield the desired product.

For the synthesis of polymers of Formula III in which and R2 are 3-methylammoniopropyl and methyl respectively in ratios varying from 5:95 to 95:5, the procedure is essentially the same as described above in which the poly-[ (methylimino)trimethylene ] s first reacted with a limiting amount of l-bromo-3-chloropropane and then with an excess of methyl bromide.

EXAMPLE XXXVI Poly-[£Methyl- ( 3-dimethylammoniopropyl) iminojtrimethylene Dichloride ] A solution of 710 mg. (10 milliequiv.) of poly-[ (methylimino)trimethylene] and 7.9 g. of l-bromo-3-chloro-propane in 35 ml. of dimethylformamide is heated at 75°C. for sixteen hours. The mixture is concentrated under re-duced pressure, suspended in 10 ml. of methanol and treated with 2.3 g. (50 mmoles) of dimethylamine at 50 °C. in a sealed tube. The reaction mixture is concentrated under reduced pressure, taken up in water and passed through a 50 ml. column of Dowex 1-X2 ion exchange resin (40 mmoles of chloride ion) yielding poly-[ methyl- (3-dimethylammonio-propyl) imino^trimethylene dichloride].

Alternatively, a solution of 710 mg. (10 milli-equiv.) of poly (nethylimino)trimethylene] in 35 ml. of di-methylformamide is treated with 6.6 g. (40 mmoles) of 3-di-methylaminopropyl bromide at 50 °C. for six hours. The product is isolated by filtration, taken up in water and passed through a 50 ml. column of Dowex 1-X2 ion-exchange resin (40 mmoles of chloride ion) yielding the 3-dimethyl- For the synthesis of polymers of Formula III in which and are 3-dimethylammoniopropyl and methyl respectively in ratios varying from 5:95 to 95:5 the proce- dure is essentially as described above in which the poly-[(methylimino)trimethylene] is treated with either a limiting amount of l-bromo-3-chloropropane or 3-dimethylaminopropyl bromide and then with an excess of methyl bronide.

EXAMPLE XXXVII Poly-[-^Methyl- ( 3-trimethylammoniopropyl) iminojtrimethylene Dibromide ] A solution of 710 mg. (10 milliequiv.) of poly-[ (methylimino)trimethylene ] and 10.4 g. (40 mmoles) of 3-bromo- propyltrimethylammonium bromide in 40 ml. of purified dimethyl- formamide is heated at 75 °C. for twelve hours. The product is isolated by filtration, washed with acetone and dried under reduced pressure, yielding 1.8 g. of poly-[- methyl- ( 3-trimethylammoniopropyl) imino^triraethylene dibromide].

EXAMPLE XXXVIII Poly- [ ^Methyl- ( 3-trimethylammoniopropyl) imino^trimethylene Dichloride ] A solution of 1.66 g. (5 milliequiv.) of poly- [ methyl- (3-trimethylammoniopropyl) iminb^trimethylene di- bromide] in 85 ml. of water is passed slowly through a column containing 50 ml. (40 mmoles) of Dowex 1-X2 resin on the chloride ion cycle. Water is then passed through until no chloride ion can be detected in the eluate. Concentra- tion of the combined eluate to dryness at 50 °C. yields 1.1 g. of poly- l methyl- (3-trimethylammoniopropyl) ir.ino-trimethylene dichloride].

For the synthesis of polymers of Formula III in - cedure is essentially as described above in Example XXXVII in which the poly-[ (methylimino) trimethylene ] is reacted with a limiting amount of 3-bromopropyltrimethylammonium bromide and then with an excess of methyl bronide.

EXAMPLE XXXIX Poly- [ Methyl- (carboethoxymethyl) imino} trimethylene Chloride] _ A solution of 1 g. (14 milliequiv.) of poly-[ (methylimino) trimethylene ] and 8.8 g. (56 mmoles) of ethyl o-bromoacetate in 20 ml. of dimethylfonaamide is heated at 50°C. for twelve hours. The mixture is diluted with five volumes of ether and the product is isolated by filtra-tion. The product is taken up in water and passed through a 75 ml. column of Dowex 1-X2 ion-exchange resin (60 mmoles chloride ion) and the eluate is concentrated under reduced pressure to yield poly- [^methyl- (carboethoxymethyl) imino- -trimethylene chloride].

EXAMPLE XL Poly- [-^Methyl- (carboxylatomethyl) imino"trimethylene ] A solution of 500 mg. (7 milliequiv.) of poly- [ (methylimino) trimethylene ] and 4.4 g. (28 mmoles) of ethyl o-bromoacetate in 10 ml. of purified dimethylformamide is heated at 50 °C. for 12 hours. The reaction mixture is con-centrated to dryness under reduced pressure, and the residue is treated with 28 ml. of IN sodium hydroxide overnight.

Next, 21 ml. of IN hydrochloric acid is added to the mixture and the solution is desalted in an Amicon filter cell equip-ped with a UM2 Diaflo Ultrafilter. The solution is concen-trated to dryness at 50 °C. yielding 650 mg. of poly- [^methyl- (carboxylatomethyl) imino}trimethylene ] .

For the synthesis of polymers of Formula III in which and are carboxylatomethyl and methyl respectively in ratios ranging from 5:95 to 95:5 the procedure is essen-tially as described above in which poly- [ (methylimino) tri-methylene] is reacted with a limiting amount of ethyl-a-bromoacetate and then with an excess of methyl bromide.

EXAMPLE XLI Poly- [-^Methyl- (carbamylmethy1) imino^trimethylene Chloride A solution of 355 mg. (5 milliequiv.) of poly-[ (methylimino) trimethylene ] and 3.5 g. (25 moles) of 2-bromo-acetamide in 10 ml. of dimethylformamide is heated at 60°C. for 15 hours. The product is isolated by filtration, taken o up m water and passed through a 25 ml. column of Dowex 1-X2 ion exchange resin (20 mmoles chloride ion) yielding poly- [-£methyl- (carbamylmethyl) iminoj-triiuethylene chloride].

For polymers of Formula III in which and are carbamylmethyl and methyl respectively in ratios varying from 95:5 to 5:95, the procedure is essentially as described above in which the poly-[ (methylimino) triraethylene ] is treated first with a limiting amount of 2-broraoacetaiuide and then with an excess of methyl bromide.

EXAMPLE XLII Poly- [/Methyl- ( 3-N2-methylcarbamidino ropyl) iminoj- trimethylene Chloriae Hydrochloride ] A solution of 710 mg. (10 milliequiv.) of poly- [ (methylimino) trimethylene ] and 12.5 g. (40 mmoles) of 4-bromo- 2 N -methyl-N-benzyloxycarbonylbutyramidine in 50 ml. of di-methylformamide is heated at 75 °C. for 16 hours. The rnix-ture is concentrated under reduced pressure arid the product is extracted into 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 of Dowex 1-X2 ion-exchange resin (80 mmoles of chloride ion) yielding the desired product containing the chloride counter ion.

For compounds of Formula III in which R^ and R2 2 are 3-N -methylcarbamidmopropyl and methyl respectively in ratios of 95:5 to 5:95, the procedure described above is employed in which the poly- [ (methylimino) trimethylene ] is 2 treated first with a limited quantity of 4-bromo N -methyl- N-benzyloxycarbonylbutyramidine and then with an excess of methyl bromide.

EXAMPLE XLIII Poly- [-{Methyl- (3-guanidinopropyl) iminoj trimethylene Chloride Hydrochloride ] A solution of 355 mg. (5 milliequiv.) of poly-[ (methylimino)trimethylene] and 5.6 g. (25 mmoles) of N^-3- 3 bromopropyl-N -nitroguanidine in 15 ml. of dinethylformamide is heated at 75 °C. for 16 hours. The mixture is concen- trated at reduced pressure and the product is extracted into 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 Dowex 1-X2 ion-exchange resin (40 mmoles of chloride ion) yielding the desired product containing the chloride counter ion.

For compounds of Formula III in which and R2 are 3-guanidinopropyl and methyl respectively in ratios varying from 95:5 to 5:95, the procedure described above is applied in which the poly-I (methylimino) trimethylene] is first treated with a limiting amount of N -3-bromopropyl- 3 N -nitroguanidine and then with an excess of methyl bromide.

EXAMPLE XLIV Poly- [^Methyl- (2-oxopropyl) imino}trimethylene Chloride] A solution of 355 mg. (5 milliequiv.) of poly-[ (methylimino) trimethylene ] and 2.3 g. (25 mmoles) 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 in which and are 2-oxopropyl and methyl respectively in ratios varying from 95:5 to 5:95, the procedure described above is followed in which the poly- [ (methylimino) trimethylene ] is treated first with a limiting amount of chloropropanone-2 and then with an excess of methyl bromide. Treatment of the product with Dowex 1-X2 on the chloride ion cycle gives the product con-taining the chloride ion exclusively.

EXAMPLE XLV Poly- [^Methyl- (benzyl) imino^trimethylene Chloride ] A solution of 710 mg. (10 milliequiv.) of poly-[ (methylimino) trimethylene] and 6.8 g. (40 mmoles) of benzyl bromide in 15 ml. of dimethylformamide is heated at 50°C. for 16 hours. The product is isolated by concentration of the reaction mixture under reduced pressure and extraction into water. The aqueous solution is passed through a 25 ml. column of Dowex 1-X2 ion exchange resin (40 "roles of chloride ion) yielding the desired product containing the chloride counter ion.

For polymers of Formula III in which R^ and 2 are benzyl and methyl respectively, the procedure described above is followed in which the poly-[ (methylimino) trimethylene ] is first reacted with a limited amount of benzyl bromide and then an excess of methyl bromide.

EXAMPLE XLVI Poly- [-^Methyl- ( 1-propen-3-y1) imind^trimethylene Chloride ] A solution of 426 mg. (6 milliequiv.) of poly-[(met-hylimino)trimethylene] and 3.7 g. (30 mmoles) of 3-bromo- propene-1 (allyl bromide) in 12 ml. of dimeth lformamide 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 of Dowex 1-X2 ion exchange resin (32 mmoles of chloride ion) and the eluate is concen- trated under reduced pressure yielding the desired product containing the chloride counter ion.

For compounds of Formula III in which R^ and R2 are l-propen-3-yl and methyl respectively in ratios vary- ing from 95:5 to 5:95, the procedure is similar to that described above in which the poly-[ (methylimino) trimethylene ] is reacted with a limiting quantity of 3-bromopropene-l and then an excess of methyl bromide.

EXAMPLE XLVII Poly- [^Methyl- (l-propyn-3-yl) imino-trimethylene Chloride ] A solution of 710 mg. (10 milliequiv.) of poly-[ (methyliinino)trimethylene ] and 3.6 g. (30 mmoles) of 3- bromopropyne-1 (propargyl bromide) in 12 ml. of dimethyl- formamide is heated at 50 °C. for 16 hours. The product is isolated by filtration, dissolved in water and passed through a 40 ml. column of Dowex 1-X2 ion exchange resin (32 mmoles of chloride ion) yielding the desired product containing the chloride counter ion.

As for previous examples, polymers of Formula III in which R.j= l-propyn-3-yl and R2= CH3 in ratios ranging from 5:95 to 95:5 are synthesized by first treating the poly-[(methylimino)trimethylene ] with a limiting amount of propargyl bromide and then with an excess of methyl bromide.

EXAMPLE XLVIII Poly-[-{Methyl- (2,2,2-trifluoroeth l) imino~}triniethylene Chloride1 A solution of 355 mg. (5 milliequiv.) of poly-[(methylimino)trimethylenel and 6.2 g. (22 mmoles) of 2,2,2- trifluoroethyl trichloromethylsulfonate in 15 ml. of dimethyl formamide 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 of Dowex 1-X2 ion exchange resin (20 mmoles chloride ion) and the eluate is concentrated under reduced pressure yielding the desired product contain- ing the chloride counter ion.

For polymers of Formula III in which R^ and are 2 ,2 , 2-trifluoroethyl and methyl respectively in ratios varying from 95:5 to 5:95, the procedures described above are employed in which the poly-t (methylimino) trimethylene ] is first treated with a limiting quantity of 2 ,2 ,2-trifluoro- ethyl trichloromethylsulfonate and then with an excess of methyl bromide.

EXAMPLE XLIX Poly- [-^Methyl- ( l-a->-glucopyranosyl) iminq}"trinethylene Chloride] A solution of 535 mg . (5 milliequiv.) of poly-[ (methylimino) trimethylene] and 10.3 g. (25 mmoles) of tetra-0-acetyl-a-/)-glucopyranosyl bromide in 25 ml. of di-methylformamide is heated at 50°C. for 16 hours. The pro-duct is isolated by dilution with ether followed by filtration. The product is taken up in 5 ml. of water and 2 ml. of 10% hydrobromic acid is added, frfter being allowed to stand overnight, the solution is diluted to a volume of 100 ml. with water and placed in an Amicon filter cell containing a UM-2 Diaflo Ultrafilter. After 800 ml. of filtrate is collected, the retentate is concentrated to a 50 ml. volume and passed through a 25 ml. column of Dowex 1-X2 ion exchange resin (20 mmoles of chlorioe ion) . Concen-tration of the eluate yields the desired analog containing the chloride counter ion.

For compounds of Formula III in which and are l-a->-glucopyranosyl and methyl respectively in ratios varying from 95:5 to 5:95, the procedure described above is followed in which the poly- [ (methylimino) trimethylene] is treated first with a limiting quantity of tetra-O-acetyl-a-P-glucopyranosyl bromide and then an excess of methyl bromide.

The procedures described in Examples XXVII through XLIX are equally applicable for conversions of poly-[ (methyl-imino) ethylene ] to the corresponding quaternary analogs and are followed using the corresponding milliequivalents of poly- [ (methylimino) ethylene] in place of the poly-t (methyl- EXAMPLE L Poly- [-£Methyl- ( 2-trimethylammonioethyl) imino^ ethylene Dibromide ] A solution of 570 rag. (10 milliequiv.) of poly-[ (methylimino) ethylene] and 9.9 g. (40 mmoles) of 2-bromo-ethyltrimethylammonium bromide in 40 ml. of dimethyIfor-mamide is heated at 75 °C. for 12 hours. After being cooled, 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 the oral administration of remarkably small dosages of the polymers of this invention. This enables a flexibility of formulation previously unavailable. The polymers can be finely divided powders and suitably used as such or preferably admixed with varying amounts of solid carrier agents such as colloidal silica, starches, sucrose, talc, lactose, cellulose, or modified cellulose, dry milk powder, protein powders such as soy flour, and the like. These are preferably made into unit dosage forms such as tablets, filled gelatin capsules, or a foil or paper envelope containing the premeasured dose which can include supplementary vitamins and minerals, and which can be readily torn open and added to edible liquids such as fruit juices or other beverages. The unit dose composition may comprise from 10% to 99% by weight of polymer, the remainder being carriers, flavorings, excipients, flow agents and the like. In such a unit dose, the active polymer may comprise from 0.1 gm. to up to 10 gms. in powder packets.

Also suitable are aqueous solutions or suspensions oil for oral ingestion as such or as an aqueous emulsion. These may also be encapsulated.

As hereinbefore stated the total daily dosage of bile acid binding polymer is preferably divided into portions and taken before each meal and prior to bedtine. This regimen provides for maximum resin contact tire during periods of highest intestinal bile acid concentrations.

The polymers of this invention may be used alone, or, if desired, can be compounded together with triglyceride synthesis inhibitors or other bile acid binding agents for particular treatments. In addition, as heretofore stated, the polymers described herein form salts with the acids of clofibrate and halofenate, which salts are useful in cardio-vascular disease therapy. The following examples are illus-trative of the dosage forms which can be employed in the practice of our invention. Those skilled in the art of pharmaceutical compounding will be aware of variations which can be practical without departing from the spirit of our invention. It is anticipated that multiple dosages, e.g., two or three tablets or capsules can be taken at one time if higher dosages are prescribed.

Additional ingredients which may comprise the carrier portion of the compositions of this invention, can also have pharmacological activity and can include other choleretic agents such as tocaiaphyl florantyrone ; taurine; and glycine; hypocholesteremic agents such as nicotinic acid; the D-isomer of 3 , 31 , 5-triiodothyronine ; thyroxine-like compounds such as sodium L-thyroxin and sodium D-thyroxine; triiodothyropropionic acid; acid and 3-methyl-5-isoxazolecarboxylic acid; fecal softeners such as poloxalkol and dioctyl sodium sulfo-succinate; as well as unsaturated fatty acids such as linoleic acid, arachidonic acid and linolenic acid; edible vegetable oils such as corn oil and safflower oil.

POWDER PACKETS Linear, unbranched and non-cross-linked poly-[ (dimethylimino) ethylene chloride] molecular weight about 20,000 is finely powdered and blended with 1% by weight of lactose powder. Aluminum envelopes containing a paper bag liner are individually filled with 0.55 g. of the mixture and sealed against moisture to prevent caking.

In place of the poly- [ (dimethylim no) ethylene chloride] there can be substituted therefor poly- [ (2-hydroxyethyl) methyliminoeth lene chloride] or other polymers of our invention, having various molecular weights from about 1500 to about 50,000 and higher and comprising polymers of a single average molecular weight or mixtures of varying molecular weights, so long as generally in excess of about 1500.

HARD GELATIN CAPSULES The same dosage, i.e, .55 g., of poly-[ (dimethyl-imino) ethylene chloride] containing 1¾ by weight of lactose as described above is filled into the appropriate size hard gelatin capsules.

Alternatively, a dry filled capsule can be pre-pared from the following components: poly- [ (trimethylammonioethyljmethylininoj- 300 mg. ethylene chloride] Dry filled capsules can likewise be prepared using any of the other novel polymers set forth in this specifica-tion. If capsules of lower potency are to be prepared, the capsule size can be decreased or additional corn starch or other diluent employed. When using smaller ar.ounts of active ingredient it is anticipated that a multiple capsule dose can be administered.

COMPRESSED TABLETS A dry blend is prepared with the following components: poly- [ (dimethylimino) ethylene chloride] 1 kg. sucrose, powdered 30 gms. colloidal silica 10 gms. carbowax-4000 30 gms. Four thousand tablets are pressed therefrom by direct com-pression each of which tablets contains 250 mg. of the ionene polymer.

Likewise, compressed tablets are prepared such that each tablet contains: poly- [ (dimethylimino) ethylene chloride] 300 mg. corn starch 30 mg. polyvinylpyrrolidone 10 mg. magnesium stearate 3 mg.

After tableting, a plastic film can be applied to the tablets to seal them from moisture in ways well known in the art.

In addition, an enteric coating may be applied, if desired. Such a coating may comprise fats, fatty acids, waxes and mixtures thereof, shellac, ammoniated shellac, and cellulose acid phthalates applied by techniques well known and accepted.

In place of the poly- [ (dimethyl) irninoethylene chloride], there may be substituted any of the polymers of our invention.

Other binding agents may be used in place of sucrose, such as dextrose, lactose, methyl cellulose, natural and synthetic gums, and the like. Talc can replace the calcium or magnesium stearate. A variety of readily available non-toxic anti-caking agents may be sub-stituted for the colloidal silica.

Other lubricants, diluents, binders, coloring agents, flavoring agents and disintegrators can be used as are known in the art employing wet or dry granulation techniques, direct compression, spray drying and the like.

If desired, a chewable tablet can be prepared from preferably microencapsulated polymer particles by dry granu-lation as follows: In Each Tablet microencapsulated poly-[ (dimethyl- imino) ethylene chloride] 750 mg. mannitol 300 mg. sodium saccharine (or other artificial sweetener) 2 mg. oil of peppermint 1 mg. carbowax-4000 15 mg. microcrystalline cellulose 100 mg.

The polymers of this invention are additionally especially useful throughout their molecular weight range when employed as agents for the flocc lation of colloidal particles in liquids such as, for example, as fresh and waste water. They can also be used as retention aids when added to paper furnish during the papermaking operation. Furthermore, the polymers are useful as antibacterial and antistatic agents and as the latter, can be eiaployed in the treatment of cotton, wool, and synthetic fibers. These polymers can also be used as fabric softeness , and dye assists, especially for the binding of anionic type dyes. In addition, they can be used as viscosity builders, as well as adding antibacterial properties to non-ionic and cationic detergent formulations, cosmetics, hair sprays and similar applications. When so used, the polymers of this invention are employed in a like quantity and in an analogous manner to conventional known materials used for such purposes.

When employed as a clarifying or flocculating agent, the polymers of this invention are preferably dis-solved or dispersed in an aqueous medium and added to the water to be treated in an amount of from 0.5 lb. to 2 lb. of polymer for each 1,000 gallons of water to be treated.

In general, the polymers of this invention have a molecular weight of from 300 to 50,000 and more. While suitable for use as flocculating agents and the like, those polymer molecules having molecular weights below 1,500 are not suitable as bile acid binding agents, and such polymer molecules can be separated from the higher weight molecules by known methods.

These polymers are administered orally in an effective bile acid binding dose. For lowering blood serum cholesterol levels, generally a single or multiple dose of from about 0.1 to 5.0 grams is suitable although doses in excess of 10 grams can be given where indicated. Such doses are also effective in relieving symptoms of biliary pruritus. Administration can be in a variety of a chewab.le or a coated tablet, or in a capsule, and can be continued for an extended course of treatment.

Generally, medication is on a daily basis with each day's dose taken in divided portions, preferably with meals .

For control of hypercholesterolemia, the particular individual dosage, given variances in metabolism and diet, is preferably arrived at through an initial determination and continued monitoring of blood serum cholesterol levels. Thus, a moderate dosage might be employed initially, and increased until the desired blood serum cholesterol level is achieved and maintained. For an initial dose, pending such individual adjustment, from 2.5 to 100 mg./kg. of body weight per day is satisfactory.

One skilled in the art will appreciate that R^, R2, R3 and when ammonioloweralkyl, loweralkylammoniolower-alkyl, diloweralkylamraonioloweralkyl can also be in the form of the free amine, namely, aminoloweralkyl, loweralkylamino-loweralkyl and diloweralkylaminoloweralk l, respectively.

Claims (9)

1. 5540IA WHAT IS CLAIMED IS: 1. A linear unbranched non-cross- linked polymer of the formula where R^ and R2 are the same or different and are hydrogen; loweralkyl; monohydroxy-substituted loweralkyl, polyhydroxy-substituted to Cg alkyl and polyhydroxy-substituted to Cg cycloalkyl; C3 to C-, cycloalkyl; C3 to cycloalkyl-substituted loweralkyl; loweralkyl-substituted to C--cycloalkyl; ammonioloweralkyl, loweralkylammonioloweralkyl; diloweralkylammonioloweralkyl; triloweralk lammonioloweralkyl; carboxyloweralkyl; carboloweralkoxyloweralkyl; C3 to alkenyl; to C-, alkynyl; aralkyl; carbamylloweralkyl ; fluoroloweralkyl, cyanoloweralkyl; guanidinoloweralkyl; carbamidinoloweralkyl; N-loweralkylcarbamidinoloweralkyl; loweralkoxyloweralkyl; loweralkylthioloweralkyl; furanosyl; pyranosyl; and loweralkanoylloweralkyl; and are the same or different and are loweralkyl; monohydroxy-substituted loweralkyl, polyhydroxy-substituted to Cg alkyl and polyhydroxy-substituted C3 to Cg cycloalkyl; C3 to C-, cycloalkyl; C3 to C-, cycloalkyl-substituted loweralkyl; loweralkyl-substituted C3 to C-, cycloalkyl; ammonioloweralkyl; loweralk lammonioloweralkyl; dilbwer-alkylammonioloweralkyl; triloweralkylammonioloweralkyl; carboxyloweralkyl; carboloweralkox loweralkyl; C3 to C-, alkenyl; C3 to C? alkynyl; aralkyl; carbamylloweralkyl; fluoroloweralk l; c anoloweralkyl; guanidinoloweralkyl; car- 15540IA bamidinoloweralkyl; N-loweralkylcarbamidinoloweralkyl ; loweralkoxyloweralkyl ; loweralkylthioloweralk 1 ; furanosyl; pyranosyl; and loweralkanoylloweralkyl where n is an integer such that the weight average molecular weight is from 300-50,000; m is the integer 0 or 1; 1 and 2 are end groups; Z is a monovalent or polyvalent counter anion; Q is ethylene or trimethylene; the symbol *'WA-indicates a bond to a plurality of the groups R3 R4 where R^, R^> R3' ^4' Q' Z, and m are as previously defined, and provided that when m is 1 and Q is trimethylene, ^, R2 , ¾2 anc^ R are not simultaneously loweralkyl.

2. A polymer according to claim 1 where the molecular weight is in excess of 1,500. 3. A polymer according to claim 1 where R^ and R2 are hydrogen . 4. A polymer according to claim 1 where m is 0. 5. A polymer according to claim 1 where R^ and R^ are loweralkyl. 6. Λ polymer according to claim 1 where R and R_ are loweralkyl. 15540IA 7. A polymer according to claim 1 where or are ammonioloweralkyl; loweralkylammonioloweralkyl; diloweralkylammonioloweralkyl ; and triloweralkylammonioloweralkyl where said ammonio cation is countered with the anion Z .

3. Λ polymer according to claim 7 where or are triloweralkylammonioloweralkyl where said ammonio cation is countered with the anion Z . . A polymer according to claim 1 where 2 or R^ are hydroxy-substituted loweralkyl or hydroxy-substituted C, to cycloalkyl. 10. Λ polymer according to claim 1 where Q is ethylene. 11. A linear unbranched non-cross- linked polymer the formula where R^ and are the same or different and are hydrogen; loweralkyl; monohydroxy-substituted loweralkyl, polyhydroxy-substituted C^ to Cg alkyl and polyhydroxy substituted C^ to Cg cycloalkyl; C^ to C-, cycloalkyl; C^ to C-, cycloalkyl-substituted loweralkyl; loweralkyl-substituted C^ to cycloalkyl; ammonioloweralkyl, loweralkylammonioloweralkyl ; diloweralkylammoniolower 15540IA alkynyl; aralkyl; carbamylloweralkyl fluoroloweralkyl , cyanoloweralkyl; guanidinoloweralkyl; carbam dinolower- alkyl; N-loweralkylcarbamidinoloweralkyl; loweralkoxy- loweralkyl; loweralkylthioloweralkyl ; furanosyl; pyranosyl; and loweralkanoylloweralkyl where n is an integer such that the weight average molecular weight is from 300-50,000; m is the integer 0 or 1; τ1 and 2 are end groups Z is a monovalent or polyvalent counter anion; Q is ethylene or trimethylene ; the symbol ΠΛ/Χ. indicates a bond to a plurality of the groups provided that when m is 1 and Q is trimethylene R^ and are not simultaneously loweralkyl. 12. A polymer according to claim 11 where and R2 are loweralkyl. 13. A polymer according to claim 11 where R^ and R2 are hydrogen. 1

4. A polymer according to claim 11 where m is ( 1

5. A polymer according to claim 14 which is poly-[ (meth limino) trimethylene ] . 1

6. A polymer according to claim 14 which is poly-[ (methylimino) ethylene] . 15540IA 1

7. A polymer according to claim 11 where or R2 are ammonioloweralkyl ; loweralkylammonioloweralkyl diloweralkylammonioloweralkyl ; and triloweralkyl-ammoniolov/eralkyl where said ammonio cation is countered with the anion Z . 1

8. A polymer according to claim 11 where or 2 are trialkylammonioloweralkyl where said ammonio cation is countered with the anion Z. 1

9. A polymer according to claim 11 where R or R2 are hydroxy-substituted loweralkyl or hydroxy-substituted cycloloweralkyl . 20. A polymer according to claim 11 where Q is ethylene. 21. A polymer according to claim 11 which is poly- [ (dimethylimino) ethylene chloride] . 22. A polymer according to claim 11 which is poly- [ methyl- (2-trimethylammonioethyl)imino } ethylene dichloride] . 23. A polymer according to claim 11 which is poly- [ (dimethylimino) ethylene ascorbate] . 24. A polymer according to claim 11 which is poly- [ (dimethylimino) ethylene 3-trifluoromethylphenoxy (4-chlorophenyl) acetate] . 15540IA 25. A polymer according to claim 11 where Q is trimethylene . 26. A polymer according to claim 25 where Z is halide. 27. A polymer according to claim 26 which is poly- [ methyl- (3-trimethylammoniopropyl) iminoJtrimethylene dichloride] . 28. A polymer according to claim 26 which is poly- [-{methyl- (3-hydroxypropyl) imino } trimethylene chloride] 29. A polymer according to claim 26 which is poly- [ methyl- (3-methoxypropyl) iminoJ-trimethylene chloride] 30. A polymer according to claim 26 which is poly- [ methyl- (3-methylthiopropyl) iminoj- trimethylene chloride] . 31. A polymer according to claim 26 which is poly- [{methyl- (2-oxopropyl) imino trimethylene chloride] . 32. A polymer according to claim 25 which is poly- [{methyl- (carboxylatomethy1) imino trimethylene] . 33. A polymer according to claim 26 which is poly- [{methyl- (carbamylmethyl) iminoJ- trimethylene chloride] . 15540IA A polymer according to claim 11 where R is methyl. 35. A polymer according to claim 34 where R is 3-trimethylammoniopropyl halide. 36. A polymer according to claim 34 where R is benzyl. 37. A method of preparing a linear, unbranched, cross- linked polymer comprising repeating units of a monomer of the formula where m is the integer 1 or 0, R' is hydrogen, loweralkyl, phenyl, naphthyl, or naphthylethyl, Q is ethylene or trimethylene and Z is a counter anion comprising reacting a polymer comprising repeating units of a monomer of the formula R' where R' and Q are as previously defined with at least a molar equivalent of a chemical reductant. 15540IA 38. A method according to claim 37 where the chemical reductant is diborane. 39. A method of preparing a linear unbranched non-cross- linked polymer comprising repeating units of a monomer of the formula where Q is ethylene or trimethylene, and Z is a counter- anion comprising admixing a polymer comprising repeating units of a monomer of the formula where Q is ethylene or trimethylene with at least one equivalent each of formaldehyde and formic acid and heating the resulting admixture at a temperature of from 30° to 100°C. for up to 100 hours. 40. A method according to claim 39 where a mixture of 97 to 100% formic acid and aqueous formaldehyde is employed. 15540IA 41. A method of preparing a linear unbranched non- linked polymer comprising repeating units of a monomer of the formula where Q is ethylene or trimethylene and Z is a counteranion comprising admixing a polymer comprising repeating units of a monomer of the formula with at least one equivalent each of formaldehyde and formic acid, and heatin the resulting admixture to a temperature of from 30° to 100°C. for up to 100 hours. 42. A method according to claim 41 where a mixture of 97 to 100% formic acid and aqueous formaldehyde is employed. 43. A method according to claim 41 where O is ethylene 44. A method according to claim 41 where Q is trimethylene . 15540IA 45. A method for making a first linear, un-branched non-cross-linked polymer comprising repeating units of a monomer of the formula where Z is a counteranion , Q is ethylene or trimethylene , m is the integer 0 or 1, indicates bonding to a plurality of the groups ~N-Q or -N-Q- , I I R3 R4 where Z, Q, and m are as previously defined and R^ and R^ are the same or different and are loweralkyl; monohydroxy-substituted loweralkyl, polyhydroxy substituted to alkyl and polyhydroxy-substituted to Cg cycloalkyl; to Crj cycloalkyl; to C-, cycloalkyl substituted loweralkyl; loweralkyl-substituted to C-, cycloalkyl;" ammonioloweralkyl ; loweralkylammonioloweralkyl ; dilower-alkylammonioloweralkyl ; triloweralkylammonioloweralkyl ; carboxyloweralkyl ; carboloweralkox loweralkyl ; C3 to C-, alkenyl; to C-, alkynyl; aralkyl; carbam loweralkyl ; fluoroloweralkyl; cyanoloweralkyl; guanidinoloweralkyl; car-bamidinoloweralkyl ; N-loweralkylcarbamidinoloweralkyl ; loweralkoxyloweralkyl ; loweralkylthxoloweralkyl ; furanosyl ; pyranosyl; and loweralkanoylloweralkyl ; comprising reactina a second polymer comprising repeating monomer units of the formula 15540IA where Q is as previously defined with: (a) when and are alike, at least 1.5 equivalents of RX where R is R^ or and X is halide or sulfonate, sulfate in an inert solvent at a temperature of from 30° C. to 100°C. and (b) when R^ and R^ are different, first reacting the second polymer with less than an equivalent of R^X in an inert solvent followed by reacting with an amount of a base which is matching to the equivalents of R^X employed to form a third polymer; then reacting said third polymer in an inert solvent with a reactant R.X such that the amounts of R X and 4 3 R4X employed are substantially equivalent to the equivalents of repeating monomer units in said second polymer. 46. A method according to claim 45 where R^ and R^ are methyl and Q is ethylene. 47. A method according to claim 45 where R^ and R. are methyl and Q is trimethylene . 15540IA 48. A method for making a first linear, un-branched non-cross-linked polymer comprising repeating units of a monomer of the formula where X is a halide, sulfate or sulfonate, Q is ethylene or trimethylene, and indicates bonding to a plurality of the groups R, X" R X~ Ι Ϊ 1 + — — Q or — N Q — I I R3 R4 where X and Q are as previously defined and R^ and ^ are the same or different and are loweralkyl; monohydroxy-substituted loweralkyl, polyhydroxy substituted to Cg alkyl and polyhydroxy-substituted to cycloalkyl; to C-, cycloalkyl; C3 to C-, cycloalkyl-substituted loweralkyl; loweralkyl substituted to C-, cycloalkyl; ammonioloweralkyl; loweralkylammonioloweralkyl ; dilower-alkylaramonioloweralky1 ; triloweralkylammonioloweralkyl ; carbox loweralkyl; carboloweralkoxyloweralkyl C3 to C-, alkenyl; to alkynyl; aralkyl; carbamyloweralkyl; fluoroloweralkyl; cyanoloweralkyl; guanidinoloweralkyl; car-bamidinoloweralkyl; N-loweralkylcarbamidinoloweralkyl; loweralkoxyloweralkyl ; loweralkylthioloweralkyl ; furanosyl; pyranosyl; and loweralkanoylloweralkyl ; and R^ and R2 are the same or different and are hydrogen, loweralkyl; monohydroxy-substituted loweralkyl, polyhydroxy-substituted 15540IA to Cg alkyl and polyhydroxy-substituted to cycloalkyl; C3 to C-, cycloalkyl; to C-, cycloalkyl-substituted loweralkyl; loweralkyl-substituted to C-, cycloalkyl; aramonioloweralkyl, loweralkylaramonioloweralkyl ; diloweralkylaramonioloweralkyl ; triloweralkylammoniolower-alkyl; carboxyloweralkyl; carboloweralkox loweralkyl; to C-, alkenyl; C3 to C-, alkynyl; aralkyl; carbamylloweralkyl; fluoroloweralkyl; cyanoloweralkyl; guanidinoloweralkyl; carbaraidinoloweralkyl ; N-loweralkylcarbamidinoloweralkyl ; loweralkoxyloweralkyl; loweralkylthioloweralkyl; furanosyl; pyranosyl; and loweralkanoylloweralkyl ; comprising reacting a second polymer comprising repeating units of the monomer where R^, R^ , and Q are as previously defined and /l/l/l ^ indicates bonding to a plurality of the groups — N Q — N Q — I or I R3 R4 with : (a) when R-^ and R2 are alike at least an equivalent of RX where R is R1 and X is halide, sulfonate or sulfate; (b) when R^ is different from R2 reacting the second polymer first with from 5 to 95% of one equivalent of R^X, followed by reacting with at least one equivalent of R2X, and then (c) optionally exchanging the anion Z for anion X on said first polymer. 15540IA 49. A method according to claim 48 where R^ and R2 are loweralkyl. 50. A method accordina to claim 48 where and R^ are loweralkyl. 51. A method according to claim 48 where R^ or R2 are ammonioalkyl ; loweralkylammonioloweralkyl ; diloweralkylammonioloweralkyl ; and triloweralkylammonio-loweralkyl where said ammonio cation is countered with an anion Z . 52. A method according to claim 48 where R2 are hydroxy-substituted loweralkyl and hydroxy-substituted cycloloweralkyl . 53. A method according to claim 48 where R R^ are methyl. 54. A method according to claim 53 where Q ethylene. 55. A method according to claim 54 where said first polymer is poly- [{methyl- (2-trimethylammonioethyl) -imino ethylene dichloride] . 56. A method according to claim 55 where said first polymer is poly- [ (dimethylimino) ethylene ascorbate] . 15540I 57. A method according to claim 55 where said first polymer is poly- [ (dimethylimino) ethylene 3-trifluoro-methylphenoxy (4-chlorophenyl) acetate] . 58. A method according to claim 53 where Q is trimethylene. 59. A method according to claim 53 where said first polymer is poly- [ methyl- (3-trimethylammoniopropyl) -imino ~ trimethylene dichloride] . 60. A method according to claim 53 where said first polymer is poly-^methyl- (3-hydroxypropyl) imino trimethylene chloride. 61. A method according to claim 53 where said first polymer is poly- [^methyl- (3-methoxypropyl) imino^ trimethylene chloride] . 62. · A method according to claim 53 where said first polymer is poly- [{methyl- (3-methylthiopropyl) imino^ trimethylene chloride] . 63. A method according to claim 53 where said first polymer is poly- [{methyl- (2-oxopropyl) imino¾ trimethylene chloride] . 15540IA 64. A method according to claim 53 where said first polymer is poly- [-^methyl- (carboxylatomethy1) imino trimethylene ] . . 65. A method according to claim 53 where said first polymer is poly- [^methyl- (carbamylmethyl) imino-trimethylene chloride]. 66. A method according to claim 48 where R^ is V methyl. 67. A method according to claim 66 where is 3- trimethylammoniopropyl halide. 68. A method according to claim 66 where R benzyl. 69. A polymer according to claim 20 which i poly- [^methyl- (carboxylatomethyl) imino^ ethylene. 70. A method according to claim 39 where Q ethylene. 71. A method according to claim 39 where Q trimeth lene. 72. A method according to claim 48 where Q trimethylene and R, , R , R^ and R. are methyl. 44957/2 73. Ά method according to claim 54 where R, , R 2' and R. are methyl 74. A linear, unbranched non-cross-linked polymer accprding to claim 1 stibstantially as described herein with reference to the examples. 75. A process for the preparation of polymers according to any of claims 1 - 36,or 74, substantially as described herein with reference to the Examples. 76. A compositio for binding bile acid in the gastrointestinal tract of mammals comprising in unit dose form from 0.1 to 10.0 grams of polymer according to claim 1 and a non-toxic physiologically acceptable pharmaceutical carrier, wherein the molecular weight of the polymer exceeds 1,500. 77. A composition according to claim 76 where the polymer is according to claim 11. 78. A composition according to claim 76, substantially as described herein with reference to the Examples.