CA1075847A - Ionene polymers and method for their preparation - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Novel polymers having a linear backbone which free from both branching and cross-linking, comprising either tertiary or quatern?ed nitrogen atoms linked to each other through ethlene, or trimethylene group. 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 polymers of an oxasoline substitution and optional quaternization of that polymer.

Description

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They are especially useful as nonabsorbable gastro-intestinal bile acid binding agents because such binding is known to reduce levels of blood serum cholesterol. All available evidence indicates that the incidence of higher than normal blood serum cholesterol levels in humans (especially in so-called Type II Frederickson patients) is associated with atherosclerosis and o-ther hypercholesteremic disease signs.
Atherosclerosis is manifes-ted by 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 athero-sclerosis, elevated blood serum cholesterol levels are the target of various control measures, including restricted and special dietary intake, inhibition of cholesterol synthesis, accelerated catabolism, prevention of gastrointestinal absorption, as well as by means of binding bile acids in the gastrointestinal 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 mecha~
nisms effect cholesterol oxidation responses depleting serum cholesterol in an effort to restore bile acid levels. Re-gardless of the uncertainty of its mechanism, the technique is well accepted. What is lacking is a convenient, efficient, non-toxic, and easily tolerated binding agent.

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~ 0~i8~7 lleretofore, a variety oE bile acid binding ayents have been employed. These include iron salts which produce insoluble precipitates with bile acids, organic bases to act similarly, and polymers having a salt-forming capability.
Absorbable precipitants, however, present 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 effec-tive 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 difficult 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 2a as bile acid binding agents cause 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 and ' continues to rise alarmingly.

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Several explanations are advanced for the inabili-ty of resins here-tofore suggested for use in hypercholesterol-emics to match bile acid uptake wi-th the efficiency of chloride capture. One view holds that smaller inorganic anions can easily reach binding si-tes. Therefore, to ma~;e a more efficient resin one should provide greater separati~n of binding sites for bulky acids. Another view holds that resins need to be more lipid-like to penetrate ln vivo micelle formations holding fa-t-like bile acids, thus leading to suggestions that decreased water solubility for resins was desirable.
Unfortunately, these concepts have produced ]ittle improvement when translated into polymer design for treating hypercholesterolemia.
We have now found that the novel polymers herein-after 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 "salt forming nitrogen" is meant a nitrogen atom, e.g., an imino 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.

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'I'he terln "urlbranched" ls interldecl to mean a polyme:r hav.ing no repeLIted monomer units extending ~rom the po:lymer backbone and the te:rm "cross-llnked" is wsed in the usual sense to denote a joining oE two backbones.
That the polymers of t:his invent.ion are linear and unbranched i9 o:E utmost importarlce in understandiny the advances macle by this invention. Thus, while some reEerences, e.g., U.S. Patent 3,308,020 disclose monomer units -tha-t are similar to the monomer units herein d.isclosed, it must be remembered that these prior art polymers, by virtue oE the materials and methods used to prepare thern, 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, notwi-thstanding the dis-~ closures contained in German Patents 1,131,694 and 1,126,396.

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~075E~L'7 The polymers of this invention are represented by the formula I:

~ )m Tl~ ~N--Q~N Q~V~ ~ T2 _ _ n wherein Rl and R2 are the same or different and are hydrogen;
loweralkyl; monohydroxy-substituted Cl to C4 alkyl, poly-hydroxy-substituted C3 to C6 alkyl and polyhydroxy-substituted C3 to C6 cycloalkyl; C3 to C7 cycloalkyl; C3 to C7 cycloalkyl-substituted loweralkyl; loweralkyl-substituted C3 to C7 cycloalkyl; ammonioloweralkyl; loweralkylammonioloweralkyl;
diloweralkylammonioloweralkyl; triloweralkylammonioloweralkyl;
carboxyloweralkyl; carboloweralkoxyloweralkyl; C3 to C7 alkenyl; C3 to C7 alkynyl; aralkyl, e.g., 2(1-naphthyl)ethyl, - benzyl; carbamylloweralkyl; fluoroloweralkyl, e.g.,~-tri-fluoroloweralkyl; cyanoloweralkyl; guanidinoloweralkyl;
carbamidinoloweralkyl; N-loweralkylcarbamidinoloweralkyl;
loweralkoxyloweralkyl; loweralkylthioloweralkyl; furanosyl;
pyranosyl, e.g., ~-D-glucopyranosyl; and loweralkanoyllower-; alkyl.
R3 and R4 are alike or different and are loweralkyl;
2Q monohydroxy-substituted Cl to C4 alkyl, polyhydroxy- ;
, substituted C3 to C6 alkyl and polyhydroxy-substituted C3 to C6 cycloalkyl; C3 to C7 cycloalkyl; C3 to C7 cycloalkyl-substituted loweralkyl; loweralkyl-substituted C3 to C7 cycloalkyl ar~onioloweralkyl loweralkylar~onioloweralkyl :

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, 155~0Y
1075~4~7 diloweralkylammonioloweralkyl, triloweralkylammonioloweralkyl;
carboxyloweralkyl; carboloweralkoxylc,weralkyl; C3 -to C7 alkenyl; C3 to C7 alkynyl; aralkyl, e.g., 2(1-naphthyl)ethyl, benzyl; carbamylloweralkyl; fluoroloweralkyl, e.g., ~-tri-fluoroloweralkyl; cyanoloweralkyl; guanidinoloweralkyl;
carbamidinoloweralkyl; N-loweralkylcarbamidinoloweralkyl;
loweralkoxyloweralkyl; loweralkylthioloweralkyl; furanosyl;
` pyranosyl, e.g.,~-D-glucopyranosyl; and loweralkanoyllower-alkyl.
n is an integer such that the weight average molecular weight is from 300-50,000;
m is O or l;
Z is a monovalent or polyvalent counter anion;
Q is ethylene or trimethylene; and the symbolfifJ~ indicates a bond to a plurality of the groups ` ( RllZ~ m - ( R2Z )m - N Q - or N Q -; and where Q, Z, m, Rl, R2, R3 and R4 have their previously defined ; meanings.
Tl and T2 are terminal groups on the polymer and ` ~ Tl is Q and T2 is ( I - Q

or a dihydro-1,3-oxazinium or a ~2-oxazolinium complex with an anion of the initiator where Rl, R3, Z, m and Q have their ].5540Ii 1~758~7 1 previous meanings, R5 i5 selected frorn the same group as 2 Rl and R3, but may he th~ s~ne or different from either

3 one or both of Rl and R3, and R* is a Eragment derivec'

4 from a solvent wherein the ring openi~g was effected, e.g., hydrogen if an aqueous treatment was employed, or an alkyl 6 if an alcohol treatment was employed. The exact nature or 7 identity of T is actually i~naterial to the invention, or 8 the utility of the polymers hereinafter described.
9 The prefix ''lower'' as used herein indicates from l to 4 carbon atoms, and as the other above-referred 11 to al~yl groups, can be a straight chain.
12 In the above, if m is 1, Q is trimethylene, and 13 Rl, R2, R3 and R4 are loweralkyl, the compouncls thus 14 described are known. Yet, the methods disclosed herein to prepare these compounds are novel. --16 In a preerred embodiment, the poly~er has the 17 structure indicated in formula II below:

( IHZ+)m ( IHZ+)m Tl---7--Q ~ Q ~ ~ T2 II
R3 R4 n 18 where ~ indicates bonding to one or more groups ( ~) (I ~) m - N - Q - or - N Q - , and R3, R~

19 Z, Tl, T2, Q, m and n have their previously ~efined meanings.
In another preferred embodiment, the pol~ner has 21 the structure ind cated in formula III be: ~w:

(ll +)m (¦2 ~)m Tl---N--Q ~ V~N Q~ ~LT2 III

CH3 CH3 n 15540~
1~584~7 1 where ~V~ indicates bonding to one or more groups ~ )m (l2 ~)~
- N - Q - or - N - Q - , and Rl, R2 Cll CH3 2 Z, Tl, T2, Q, m and n ha~e theix previously defined 3 meanings.
4 Throughout this description, Z represents an anion 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, howevex, 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 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; bicarboIIate; nicotinate;
14 glycinate; taurinate; salicylate; an~ other anions derived 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-chloro~henoxy)-2-18 methylpropionic and 3-trifluoromethylphenoxy-(4-chlorophenyl) 19 acetic acids. When such anions of physiologically active compounds are used to neutralize quatexnized 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 dosage can fall within the desired range for the physiologi-26 cally active compound.
27 The polymers o this invention are obtained 28 through a sequence of steps, the first of which is the 29 pol~merization of a ~2-oxazoline of the formula:

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5~347 C~l C-R' IV or 1 2 1l _ 1 a 5,6-dihydro-4H-1,3-oxazine of the f~rmula:

C}12 \I-R' V
CH N

2 where R' is hydrogen, loweralkyl, phenyl, naphthyl, or 3 naphthylmethyl. Preferably, R' is hydrogen.
~: 4 STEP 1 - Polymerization The polymerization of the 2-R'-.~ -oxazolines is

6 known and is reported in Polymer Journal, 3, 35 (1972).
We have found, however, that a more reliable polymerization 8 is obtained by using trifluoromethylsulfonic acid in placeg of the initiators reported in the literature. Generally, from 0.005 to 0.1 moles of trifluoromethylsulfonic acid is 11 used for each mole of a 2-R'-~2-oxazoline, with 0.01 mole- 12 of the trifluoromethylsulfonic acid per mole of 2-R'-~2-13 oxazoline being preferred.
14 The polymerization of the 2~ 5,6-dihydxo-4H-1,3-oxazine is also known and is reported in Macromolecules, 6, 16 495 (1973). The preferred initiator of the known initiators 17 is methyl iodide.
18 Generally, the polymerization of the 2-R'-~2-19 oxazolines and the 2-R'-5,6-dihydro-4H-1,3-oxazines is carried out in a closed system in an inert solvent and 21 under an inert atmosphere such as nitrogen at a pressure 22 of from 1-100 atmospheres and heating to fronl 30C. to 23 120C. for a period of from 1-12 hours. By inert solvent,29 it is meant here and elsewhere in this specification, a solvent which is not reactive under these condi~ions . ~,~.. . , . ~ .
: .:, . , , : -155~0y 1~7589~7 either with reactants, products or itself, dimethylformamide here being the preferred solvent.
After reac-tion is deemed complete, as determined by the disappearance of the -C~N- double bond, the polymerization reaction mixture, now comprising the polymer VI:

r - I Qt7 Q~ 3 VI
C=O C=O
R' R' where R', Q and n are as previously defined and T3 is " ~ R' '~ ~ -N-Q-OR or R ~
where Y is an anion from the initiator, A is hydrogen or an ; 10 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 ; 20 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 giving the polymer VII

(7 +) -( H¦Z+)m - (7 +) ~ A N Q - _7_ Q _ - I -Q-OR* VII

- H H H
_ _ n . . .

- 1~540IP
7S8g~'7 1 where ~, m, Q, Z, R*, and n have thoir previous mean-2 ings, and z is preferably a halide.
3 The alkalin~ hydrolysis is accomplished by admixing 4 the polymer with an aqueous solution of from saturated to 0.lN base, suitably alkali hydroxide and preferably sodium 6 hydroxide. The acid hydrolysis is carried out in 1 to 2N

7 aqueous mineral acid, e.g., HCl or H25O~.
~ 8 The hydrolysis is conducted with agitation and - 9 warming for at least 3 to 30 hours. Preferahly, to achieve substantially complete hydrolysis at a slight sacrifice in 11 molecular weight, the hydrolysis can be carried out in a 12 sealed vessel at a temperature of from 40C. to 180C. The 13 quantity of aqueous hydrolyzing solution is not critical, 14 provided that agitation is good and at least t,wice the theoretical amount of alkali or acid i~ employed to effect 16 the hydrolysis.
17 From the base hydrolysis, polymer VII is obtained 18 where m is O~ and the acid hydrolysis or subsequent acidi-19 fication of the base hydrolyzed polymsr gives polymer VII
` 20 where m is 1.
21 STEP 2B - Direct Reduction 22 Polymer VI is reduced directly to polymer VIII
23 by reduction of the cyl group.
(HZ ) (HZ ) (HZ ) m I + m I + m A - N - Q - - N - Q - N - Q-OR* VIII

R' R' R' , n 24 where A, Z, Q, R', R*, Z, m and n are as previously ~efined.

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~0'7~ 7 1 Preferably, th~ polymer is ~issolvetl in an inert 2 solv~nt and slowly admixed with at least a molar equivalent 3 of a chemical reductant such as diborane which also is 4 dissolved in an inert solvent. The pref~rrec solv~nts are tetrahydrofuran and mixtures thereof ~ith ethyleneglycol 6 dimethyl ether. After addition, the reaction mixture is 7 refluxed for 1-12 hours, cooled and acidified. Other reducing

8 agents which can be employed in place of ths diborane include

9 aluminum hydride, lithium aluminum hyclride, and lithium tri methoxy aluminum hydride.
11 Alternatively, the amide groups of polymer VI are 12 converted by alkylation to imino esters with triethyloxonium 13 tetrafluoroborate complex in methylene chloride at 25C.
14 The imino ester moieties are then readily reduced to tertiary amine moieties as with sodium borohydride in ethanol at 0C.
16 to 25C.
17 STEP 2C - Reductive Methylation 18 In this procedure polymer VI where R' is hydrogen 19 is heated with a mixture of more than one equivalent each of formaldehyde and formic acid, then treated with an 21 aqueous acid and concentrated to dryness under reduced 22 pressure to give polymer IX.
(¦ +)m (HlZ+)m (Iz J m R5 - N - Q _ - N Q- - N ~ Q-OR* IX

n 23 where R5, Q, Z, R*, m and n have their previous meanings.
24 The polymer to be redllctively methylated is added to a mixture of 97~ to 100% formic acid and preferably 38 26 aqueous formaldehyde, and the xeaction mixture heated to ~ 13 -. . .
~'- , ~ . , ' ',. ' ' ~758~7 1 a temperature of from 30C. to 100C. for a pcriod of from 2 20 to 100 hours. Although higher reaction temperatures 3 are not prohibited, the increasled rat~ o~ thermal decompo-4 sition of formic acid and the risk of degradation of the polymer make the use of higher temperatures less attractive.
6 The mixture is then treated with an aqueous l~neral acid, 7 preferably hydrochloric acid, and the excess formic acid, 8 formaldehyde and mineral acid are removed by concentration 9 under reduced pressure.
STEP 3 - Direct Methylation 11 Polymer VII where m is O is methylated directly 12 by heating the polymer in a mixture of moxe than one equiva-13 lent each of formaldehyde and formic acid under conditions 14 described in Step 2C to yield polymer IX where R5, Q, Z, R*, m and n have their previous meanings.
16 STEP 4 - Addition of R3 and ~ to Pol mer VII
17 For polymers of formula X in which R3 and R4 are 18 the same, polymer VII where m is O is txeated with an excess 19 r~nging from 1.5-8 equivalents, and preferably 4 equivalents, of an alkylating agent RX in an inert solvent at tempera-21 tures ranging from 30C. to 100C. The reaction is carried 22 out by dissolving the polymer in an inert solvent such as - 23 alcohols, ketones, or dimethylformamide. Preferred solvents 24 include methanol, acetone and dimethylformamide, and pre-ferred temperatures ar~ be~ween 50C. to 75C. This results 26 in a polymer of formula X in which A, Q, Z, R* and n have 27 their previous meanings and m is 1 an-~ Z is X . Treat-28 ment of polymer X with exactly one equivalent of base yields 29 polymer X in which m is 0.
For polymers of formula X in which ~ and ~ are 31 different, polymer VII where m is O is treated with less ' . ' -: ` -S~7 1 than an equivalent ~mount of an alkyla-ting ayent R3~ and 2 then after neu~ralization with a matching equivalent of 3 base the intermediate is treated with sufficient R~X to 4 complete alkylation. Both reactions are corducted in an inert solvent at temperatures ranging from 30C. to lOO~C.
6 The reactions are conducted by dissolving the polymer in 7 an inert solvent such as alcohols, ketones or dimethylfor-8 mamide. Preferred solvents include methanol, acetone and g dimethylformarnide, and preferred temperatures are between 50~C. to 75C. Acid neutralization forms polymer X in ll which A, Q, Z, R* and n have their previous meanings and m 12 is l, and Z is X . Treatment of pol~ller X with exactly 13 one equivalent of base yields pol mer X in which m is 0.
/HZ ~ ~HZ ~ /HZ ~ (HZ
~I +~ ~I +~ m ~I +/ m ~¦ +/~
A -N- Q - - N - Q ~J~ N - Q~ ~N - Q-OR* X
R3 R3 R4 n R3 14 STEP 5 - Quaternization - Additio of R , R

Polymer VIII, from Step 2B, polymer IX, from Step 16 2C or Step 3, or polymer X, from Step 4, usually obtained . , .
17 as their acid addition salts (m=l), are converted to the 18 free base form (m=0) on treatment with an equivalent amount l9 of base. At this stage, it is convenient, though not necessary to remove any inorganic salts by ultrafiltra-21 tion techniques. This has the added advantage of also 22 eliminating any other undesirable lower molecular weight 23 material. The a~ueous solution of the polymer is then 24 concentrated under reduced pressure and the product is dried prior to the quaternization reaction that leads to 26 polymers of formula I. The quaternization reaction is ~' ' ' ' . ' .

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1 accomplished in an inert solvent such as an alcohol, ketone 2 or dimethyl~ormamide. Methanol, acetone and dimethylformamide 3 are preferred solvents. The quaternizing agents are usually 4 halide-containing compounds, preferably bromo compounds;
other alkylating agents such as toluenesulfonate esters or 6 trichloromethylsulfonate esters can also be employed. When 7 Rl and R2 are the same, a reasonable excess of the alkylating 8 agent RX is employed; when Rl and R2 are different, the g polymer is first treated wi~h a limiting amount ~5~ to 95%
of equivalence) of RlX. After that reaction is complete, the 11 product is treated with an excess of reagent R2X. rlhen the 12 alkylating reactivities of the reagent ~lX and R2X are the - 13 same, the reaction may be carried out in a mixture of RlX
14 and R2X in a single step. The RlX and R2X may be simple alkyl halides or may also carry other functional groups which do 16 not interfere with the quaternization reaction. ~ simple 17 but by no means exhaustive list of acceptable quaternization 18 reagents includes haloalkyl acid esters, haloalkyl acid amides, haloketones, fluoroalkyltrichloromethylsulfonates, alk~l halohydrins, aralkyl halides, a~monioalkyl halides, 21 loweralkyl-substituted ammonioalkyl halides, alkoxyalkyl 22 halides, alkylthioalkyl halides, allyl halides, and propar~
23 gyl bromide-24 The reaction is usually carried out by heating a solution of the polymer and alkylating agent in methanol, 26 acetone or dimethylformami~e at 35C. to 100C. for three 27 to sixteen hours. Wi~h particularly reactive alkylating 28 agents, a reaction temperature of 50C. is en~ployed. The 29 product is usually isolated directly by filtration, but in .

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~07S8~7 1 some instances it is expedient to clil~lte the reaction mixture 2 with several volumes of eth~r prior to f iltr~tion. The 3 product is usually partially dried, ground to a powder and 4 then dried under reduced pressure at ternperatures of from 25C. to 60C.
6 STEP 6 - Ion Exchange 7 The anions on polymer I are generally limited to 8 halide by the techniques of the prior steps. The full range 9 of polymers where the anion Z cliffers from halide can be obtained by dissolving polymer I having a halide anion in 11 water, alcohol, or mixtures thereof in any proportion and 12 passing the solution through a bed of anion exchange resin, 13 either a synthetic or a zeolite type, where the halide ion is 14 exchanged and replaced by Z . The anion exchange method em-ploying a resin technique can be direct, that is, exchanging 16 halide ion for Z or one can first exchange halide ion for 17 OH and then either by a subsequent ion exchange or simple 18 neutralization exchange OH for Z .
19 Additionally, chemical exchange tec~miques can be employed when a precipitate of a metal halide is less soluble 21 than the added metal salt ~Z. The precipitated metal halide 22 can then be filtered from the soluble polymer I.
23 A simple example of the latter technique involves 24 treating a solution of polymer I containing the bromide counter ion with an excess of freshly precipita*ed silver 26 chloride. After the halide anion exchange is complete, the 27 mixture of silver chloride and silver bromiæe is removed by 28 filtration leaving a solution of polyTler I containing the 29 chloride counter ion. Alternatively, polymer I where Z is sulfate can be treated with solutions of water soluble cal-31 ci~m or barium salts. Thus, sulfate can be replaced with 32 nitrate and the precipitate of barium sulfate removed.

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1 ~X~PL~. I
. . .
2 Poly-[(Formimino)eth~lene3 3 ~ solution of 44 g. of ~2-oxazoline and 870 mg.
4 of freshly distilled boron trifluoride etherate in 175 ml.
of purified dimethylormamide is placed in a pxessure 6 reactor containing a glass liner and the system is purgad 7 with nitrogen. The mixture is heated at 80C. for five 8 hours and then diluted with methanol c~nd filtered yielding ; 9 30 g. of the poly-[(fonmimino~ethylene] pol~ler. In a five-hour reaction period at 80C. and boron trifluoride etherate 11 catalyst at 0.01 mole ratio to that of ~2-oxazoline, the 12 yield of solid polymer ranges from 13.2% to at least 68~.

13 EX~LE II
:
14 Poly [(Fo_mimino)ethylene]
A solution of 217 g. (3.06 noles) of ~2-oxazoline 16 and 4.6 g. (0.03 moles) of trifluoromethylsulfonic acid in 17 800 ml. of purified dimethylformamide in a sealed tube and , .
18 under a nitrogen atmosphere is heated at 90C. and agitated 19 for five hours. After being cooled, the mixture is diluted with 1200 ml. of anhydrous methanol and the product is iso-21 lated by filtration. The product is washed with methanol 22 and then ether prior to being dried under reduced pressure.
23 This reaction yields 150 g. of poly-[(formimino)ethylene].

Poly-[(Acetim _o~ethylene]
.. : .
:- 26 A 1 g. sample of 2-methyl-~2-oxazoline is charged 27 into a Carius combustion tube with two drops of boron -~
28 trifluoride etherate (~8%). The tube is thoroughly flushed 29 with nitrogen, flame-sealed, and placed in a tube furnace at 160C. for 20 hours. The poly-[~acetimino)ethylene]

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1 polymer is a glassy, nearly colorless rc~in with a melting 2 range of 155~C.-175C. The polymer is readily soluble in 3 methylene chloride.

Poly-[(Butyrimino~ethylene3 6 In this example, an N-acylethyleneimine is poly-7 merized using a single catalyst system which also causes 8 rearrangement to an intermediate oxazoline.
9 N-Butyrylethyleneimine, 10 cc., anZ, BF3-EtO, 0.05 cc., in an evacuated tube is heated at 60C. for four hours.
11 The resulting solid is dissolved in 100 ml. CIIC13, precipi-12 tated by the addition o~ petroleum et'ner, redissolved in 13 CHC13 and reprecipitated by petroleum ether. The precipitate 14 is dried yielding 6.3 g. o~ poly-[(butyri~ino)ethylene]
having a reduced viscosity of 0.15 in a 1~ solution in 16 benzene, and m.p. 150C.
17 In an analogous manner but emPloyincr:
18 N-benzoylethyleneimine 19 2-isopropyl-~ -oxazoline 2-cyclohexyl-~ -oxazoline 21 2-naphthyl-~2-oxazoline 22 2-~-tolyl-~-2-oxazoline ; 23 there is obtained the corresponding 24 poly-[(benzoylimino)ethylenel poly-[tisobutyrimino)ethylene]
26 poly-[~cyclohexanoylimino)ethylene]
27 poly-~(naphthoylimino)ethylene]
28 poly-[(toluoylimino)ethylene]

' . - , .

-_ 15540I
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1 E~AMPL~ V
2 Poly-[(Ben~oylimino)~thy~lene3 3 2~Phenyl-2-oxazoline (1.1322 g., 7.60 x 10 3 4 mole) is charged into a Carius combustion tub~ with 7.69 x 10 5 mole of boron trifluoricle in the form of a dimethoxy-6 ethane solution. After evacuation, flushing with nitrogen 7 and sealing, the sample is heated at 150C. for two hours.
8 One gram of the resulting light yello~ glassy polymer i5 g ground to a fine powder and dissolved in 25 ml. of methylene

10 chloride. This solution is adde~ to 75 ml. of n-hexane that

11 is being stirred vigorously to give a thick, white precipi-

12 tate. The material is filtered and reprecipitated two more

13 times in the same manner to yield a fine, white powder. The

14 recovery of purified poly-[(benzoylimino)ethylene~ polymer is 80%. The molecular weight of this polymer is 7500.
.

17 Copolymerization of Equimolar Mixtures of 2-Phenyl-2-18 oxazoline and Other 2-Substituted-2-oxazolines `

19 Equimolar monomer concentrations of 2-phenyl-2-oxazoline and respectively 2-benzyl-2-oxazoline; 2-methyl-21 2-oxazoline; and 2-isopropyl-2-oxazolin~ at concentrations 22 of 1.5 mole/liter in N,N-dimethylacetamide are each heated 23 at 135C. for approximately two hours using 2-phenyl-2-24 oxazolinium perchlorate as an initiator. The resultant poly-[(acylimino)ethylenel copolymers vary randomly as to 26 content of N-acyl groupsO The 2-phenyl-2-oxaæoline gives 27 rise to the N-benzoyl derivative; thQ 2-benzyl-2-oxazoline ; 28 forms the N-phenylacetyl derivative and the 2-methyl 29 analog ~orms the N-acetyl derivative. The composition ': .

~7~8~7 1 of the copol~mer regarcling the degree of randomness is 2 influenced by the relative reaction rates of the various 3 monomers. Since the resulting polymers may be for produc-4 tion of linear poly-(e~hyleneimine), the diff~rent acyl group composition is without significance b~cause acyl groups are removed by hydrolysis. They can, of course, l)e reduced 7 directly as described in a subsequent example.

8 EX~MPLE VII
g Poly-(Iminoethylene) The hydrolysis of a poly-[~acylimino)ethylene~ is 11 accomplished by acid or base hydrolysis.
12 (a) Illustrating base hyclrolysis, a solution of 13 3 g. of poly-[(formimino)ethylene] and 3 g. of sodium hydroxide 14 in 35 ml. of water is heated with stirring at 98C. for three hours The solution is cooled to room tempexature and the 16 white solid which precipitates is isolated by filtration, 17 washed thoroughly with water and dried in vacuo, yielding 18 1.6 g. of poly-(iminoethylene).
19 (b) A 1.29 g. sample of poly-[(acetimino)ethylene]
is added to S0 ml. of approximately lN sodiun hydroxide.
21 The polymer is virtually insoluble in base at room temper-22 ature; however, after being refluxed 26 hours the reaction 23 n~xture becomes homogeneous. Cooling to room temperature 24 causes the reaction mixture to gel to a white mass.
~ydrolysis is approximately 65~ complete. The non-acylated 26 poly-liminoethylene) is purified by repeated precipitation, 27 i.e., solution into acidl filtration from partially acety-28 lated poly-(iminoethylene) and neutralization of the 29 filtrate.
(c) A 1 g. sample of poly-[(acetimino)ethylene] is 31 dissolved in 50 ml. of lN sulfuric acid. A homogeneous . ~

1554OI~

~7~i89L7 1 mixture results ~hich is heated under r~fluY for 3.5 hours, 2 the odor of acetio acid becoming apparent. After this 3 time, the titration of an aliquot portion with lN sodium 4 hydroxide indicates a 27~ completion of hydrolysis. After 21 hours at reflux, hydrolysis is 38~ complete.
6 Generally, a substantially complete hydrolysis is 7 obtained by conducting the hydrolysis as above, but in a 8 sealed tube at 120C., or higher temperatures.
g The poly-[(acylimino)ethylenes] ar~ reduced to N-alkyl and N-aralkyl derivatives without prior hydrolysis to 11 the free ~ase. The reduoing agent of choice is diborane as 12 in the following example. Lithium aluminum hydride, lithium 13 trimethoxy aluminum hydride can also be used.

14 EX~MPLE VIII
~
16 To a solution of 200 ml. (334 mmole) of 1.67M
17 diborane in tetrahydrofuran in a 500 rnl. flask equipped 18 with a reflux condenser, dropping funnel, magnetic stirrin~
19 bar, and maintained under nitrogen is added ]7 g. (200 mmole/monomer unit) of poly-[(acetimino~ethylene] in 100 ml~
21 of tetrahydrofuran over 15 minutes. The temperature is 22 maintained at approximately 0C. during the addition.
23 The reaction mixture is then maintained at reflux for six 24 hours. The mixture is permitted to cool to room temperature and 50 ml. o 6M hydrochloric acid is added slowly thxough 26 a dropping funnel. The tetrahydrofuran is removed by 27 distillation at atmospheric pressure as hydro~en is 28 evolved (15.5 1., 0.6 mole) from the hydxolysis o~ the 29 amine-borane complex. Sodium hydroxide is added to precipitate poly-[(ethylimino)ethylene].

1554OI~
~0'7S~34~

1 In an analogous manner each of the polymers 2 obtained in Example IV are reacted to form respectively:
3 poly-[(benzylimino)ethylene];
4 poly-[(iqobutylimino)ethylene];
poly-[(naphthylmethylimino)ethylene3.

7 Poly-[(Methy1imino)ethylene Hydrochloride]
8 Two and five-tenths grams of poly-(iminoethylene) g is added slowly to 12 g. of 90~ formic acid and 5.5 g. of 38% aqueous formaldehyde is added. After the mixture is 11 heated at 100C. for 72 hours, it is cooled, and 5.5 ml. of 12 concentrated HCl is added. The mixture is concentrated to 13 dryness under reduced pressure, yielding 5 g. of poly-14 [(methylimino)ethylene hydrochloride].
:
EXAMPLE X
16 Poly-~(Dimethylimino~ethylene Chloride]
17 Five hundred milligrams (5.4 mmoles) of poly-- 18 [(methylimino)ethylene hydrochloride] is dissolved in 50 ml.
19 of methanol containing 291 mg. (5.4 mmoles) of sodium methoxide. The solution is cooled in an acetone-dry ice 21 bath, and 10 g. of methyl chloride is condensed into the 22 solution. This mixture is heated in a sealed tube at 80C.
23 for five hours. This mixture is concentrated to dryness 24 under reduced pressure and the product is taken up in 3 ml.
of anhydrous methanol and filtered and the solution is con-26 centrated to dryness. Dissolution of the product in methanol, 27 filtration, and then concentration to dryness is repeated 28 several times. The filtrate is concentrated under reduced 29 pressure yielding 400 mg. of poly-[(~imethylimirlo)-ethylene chloxide].

:

;"' ~' `~ ' ' ' 7S~ 7 1 EX~MPLE ~I
2 Poly-[(Dimethylimino-e-hylene Bromide]
3 A solution of 860 mg. (20 milliequiv.) of poly-4 (iminoethylene) in 30 ml. of methanol is treated with 9.5 g. (100 mmoles) of methyl bromide at 50C. for three hours.
6 The reaction mixture is concentrated to dryness under re-7 duced pressure. The residue is treated with 1.08 g. (20 8 mmoles) of sodium me~hoxide in 10 ml. of methanol and con-g centrated to dryness. The residue is taken up in 30 ml. of anhydrous methanol and treated with 9.5 g. (100 mmoles) of 11 methyl bromide; the solution is heated at 50C. for ~hree 12 hours. After concentration, the product is taken up in 13 water, and the solution is subjected to ultrailtration 14 through a VM 2 Diaflo Ultrafilter. The retentate is then concentrated under reduced pressure yielding 2.8 g. of 16 poly-[(dimethylimino)ethylene bromide].

18 PQ1Y_1 (Dimethylimino)et~ylene Methosulfate]
~
19 0.5 Gm. of poly-[(methylimino)ethylene hydrochloride]
is dissolved in 50 ml. of methanol containing 0.29 gm. of : 21 sodium methoxide. The solution is concentrated to about 22 20 ml. and 0.7 gm. of dimethyl sulfate is adcled. The solution 23 is then heated 6 hours at 50C., and the product is precipi-24 tated by pouring the solution into a large volume of acetone or by evaporation of the methanol followed by acetone wash.
, 26 The product is dried at ambient temperature under reduced 27 pressure.

29 Poly-[~(2-Hydroxyethyl)methylim ~
The procedure of Example X is followed, but there 31 is used 15.8 g. of ethylene chlorohydrin in place of the ::
~ ~ 24 -~'~

. , .
:

155~0Y
~751~'i7 .

lO g. of methyl chloride. The mixture is heated at 80 C. for five to seven hours and then freed oE solvents and excess reagents by stripping under reduced pressure. The residue is poly- ~ (2-hydroxyethyl)methylimino}ethylene chlorid ~.
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 chlorid and poly- ~ (2-hydroxypropyl)methylimino}ethylene chlorid ~.

EXAMPLE XIV
Poly- ~2-Hydroxyethylimino)ethylen ~

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 60C. for three hours. The solvent and excess epoxide are removed by stripping under reduced pressure. The residue is poly-~2-hydroxyethylimino)ethylen ~.
EXAMPLE XV
Poly- ~ (2-Hydroxybutyl)-2-hydroxyethylimino}ethylene Bromid The poly- ~2-hydroxyethylimino)ethylen ~ from the previous example is heated in 50 ml. of acetone with 20 g. of 2-hydroxybutyl bromide at 80C. to 90C. 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}-ethylene bromid ~.

':

... .

`: :

15540I~
~L075~3~7 1 EXAMPI.E XVI
2 Poly-[(Methylimino)ethylene ~Iydroch]oride]
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 100C. for 60 hours.
6 The rea~tion mixture is cooled, 210 ml. of concentrated 7 hydrochloric acid is added, and the mixture i~ concentrated 8 to dryness under reduced pressure at 50C. After the product g is washed with methanol, then ether and dried, 34.6 g. of poly-[(methylimino)ethylene hydrochloride] is obtained.

:
12 Poly-[(Methylimino)ethylene]
13 A solution containing 0.325 mole of sodium hydroxide 14 is prepared by dissolving 17.55 g. of sodium rethoxide in 400 ml. of water. To this is added 28.6 g. (Q.31 mole) of 16 poly-E(methylimino)ethylene hydrochloride], and the total 17 volume of the solution is made up to 500 ml. by the addition 18 of water. The solution is then desalted and also rid of 19 any product with a molecular weight of less than 1000 using an Amicon filter cell equipped with a UM2 Diaflo Ultrafilter.
21 Next, the solution is concentrated under reduced pressure 22 at 50C. yielding 16 g. of poly-[(methylimino)ethylene~.

,.
24 Poly-~Dimethylimi~eth~len _ romide]
A solution of 21.7 g. (0.38 mole) of poly-[(methyl-26 imino)ethylene] in 130 ml~ of anhydrous methanol is cooled 27 and 364 g. (3.8 moles) of condensed methyl brnmide is 28 added. The mixture in a glass-lined pressure reactor is .

.
' ' , ' . .

]5540I, lO'~S~3~'7 1 heated at 50C. Eor five hours. After the mixture is 2 cooled, the product is isolated by filtration, washed 3 with ether and dried under reduced pressure ~o glve 58 g.
4 of poly-[(dimethylimino)ethylene bromide].

E~LE XIX
6 Poly-[(Dimethylimino)ethylene Chloride]
7 A solution of 58 g. of poly-[(dimethylimino)-8 ethylene bromide] ~0.38 mole) in three liters of water is 9 passed slowly (10 ml./min.) through a 770 ml. column of 200-400 mesh AGl-X8 quaternary ammonium chloride resin 11 (1078 milliequivalents of Cl ). After 4200 ml. of effluent 12 is collected, it is concentrated under reduced pressure 13 at SGC.-55C. and dried to give 37 g. of poly-l~dimethyl-14 imino)ethylene chloride].

EXAMPLE XX
16 Preparation of PolY-[(dimeth~limino)ethYlene AscorbateJ
-- ._ 17 5.0 Çrams of poly-l(dimethylimino)ethylene 18 chloride~ is dissolved in 75 ml. o~ distilled water and 19 passed down a column containing 100 gms. ~0.5 mole Cl exchange capacity) of a polystyrene resin, the benzene ring 21 of which is substituted with 4-methotrimethyl ammonium 22 hydroxide (Bio Rad AG 1 x 8). Six column volumes of the 23 eluate (450 ml.) containing poly-[(di~ethylimino)ethylene 24 hydroxide] is collected, concentrated to 150 ml , cooled to 15C., and neutralized with 8.8 gms. (0.05 moles) of 26 ascorbic acid, U.S~P. The clear neutralized solution is 27 then shell frozen and lyophilized to give a white solid 28 which is readi:Ly pulverized.

.. . . .
~ ' ....... , ~

lS5~0Il 10~

1 The other ~olymers of this invention can like-2 wise be transformecl to the ascorbate salt, or by employing 3 other acids containing physiologically acceptable anions 4 in place of the ascorbic acid, there can be o}~tained the s other salts theretofore described.
6 EX~LE XXI
., 7 5,6-Dihydro-4H-1,3-oxazine 8 A mixture of 94 g. (1.13 moles) of t-butyl iso-9 nitrile, 85 g. (1.13 moles) of freshly distilled 3-amino-propanol, and 7.4 g. (0.055 mole) of silver cyanide is 11 stirred at 90C. under a nitrogen blanket for 16 hours. The 12 product is isolated from the reaction mixture by distillation 13 at 45 mm. and is purified by repeated fractionation. Usually, 14 two such fractionations suffice to yield a pure product. In this manner, 44 g. of pure 5,6-dihydro-4H-1,3-oxazine, b.p.
16 58C./ 58 mm., nD25 1.4485 is obtained and stored over 17 molecular sieves type 4A and under nitrogen.

19 Poly-~(~or_imino)trimethylene]
A solution of 44 g. (0.52 mole~ of 5,6-dihydro-4H-21 1,3-oxazine in 140 ml. of purified dimethylformamide is put 22 in a pressure tube a~d 1.52 g. (O.011 mole) of iodomethane 23 is added. The system is purged with nitrogen, sealed and 24 heated at 80C. for five hours. The mixture is cooled and diluted with ten volumes of ether, and the product is isolatea 26 by filtration. The product is washed with etller and dried 27 under reduced pressure at 75C. yielding 40 c. of poly-28 E(formimino)trimethylene, m.p. decomposes at 111C.-112C.

75~7 EXAMPLE XXI I I
2 Poly-[(Methylimino)trimethylene ~Iydrochloride]
3 A mixture of 53 g. of poly--(formiminotrimethylene), 4 1320 g. of 97~-100~ formic acid, and 308 g. of 38% aqueous formaldehyde is heated at 100C. for 120 hours. After the 6 solution is cooled, 650 mlO of concentrated hydrochloric 7 acid is added, and the mixture is concentrated to dryness 8 at 50C. under reduced pressure. The residue is triturated 9 with 400 ml. of methanol, isolated by filtration, washed with ether and dried under reduced prsssure yielding 67 g.
11 of poly-[(methylimino~trimethylene hy~rochloride].
12 E~LE XXIV
13 Poly-[(Methylimino ? trimethylene]
14 A solution 4f 67 g. (630 milliequiv~) of poly-[(methylimino)trimethylene hydrochloride] in 600 ml. of water 16 is treated with 39 g. (0.72 mole) of soaium methoxide. This 17 is simply an easy way to prepare a solution of sodium hydro-18 xide of precise normality. A corresponding volume of a 19 standardized solution of sodium hydroxide is equally adequate.
The solution is desalted and polymer with molecular weight 21 below 1,000 is removed using an Amicon filter cell equipped 22 with a UM2 Diaflo Ultrafil~er. Finally, the solution is 23 concentrated at 50C. under reduced pressure yielding 45 g.
24 of poly-l(methylimino)trimethylene].
EXAMPLE XXV
26 Poly-[(Dimethylimino)trime~hylene Bromide3 27 A solution of 14 g. (200 milliequiv.~ o~ poly-28 E(methylimino)trimethylene] and 76 g. (0.8 moles) of bromo-29 methane in 90 ml. of methanol is heated at 50C. in a sealed reactor for five hours. The product is isolatecl by filtra-31 tion, washed with methanol and then ether, ancl dried under 32 reduced pressure, yielding 28 g. of poly-[(dimethylimino) 33 trimethylene bromide].

- 155~0I
1075~

1 ~AMPI,~ ,YXVI
2 Poly-l ~ mino)trimethylene Chloride]
3 ~ solution of 28 g. (170 milliequiv.) of pol~-4 ~(dimethylimino)trimethylene bromide] in 1400 ml. of water is passed slowly through a column containing 1,000 ml. of ~owex l-X2 (Cl cycle) resin (0.8 mole). ~fter the 7 solution has passed through, water is passed through the 8 column until a ne~ative silver nitrate test is observed 9 with the effluent. The total effluent is concentrated to dryness, and the product is dried under r~duced pressure 11 yielding 17~2 g. of poly-[(dimethylimino)trimethylene 12 chloride].

14 Poly-~Methyl-(3-hydroxypropyl)imino}trimethylene Bromide]
~ solution of 142 mg. (2 milliequiv.~ of poly 16 [(methylimino)trimethylene] and 1.12 g. ~8 mmoles) of 3-bromo-17 propanol in 5 ml. of purified dimethylformamide is heated 18 at 75C. for 24 hours. The product is isolated by filtration, 19 washed with acetone and dried under reduced pressure yielding 330 mg. of poly- ~methyl-(3-hydroxypropyl)imino~trimethylene 21 bromide].

23 Pol~- ~(Methyl-~3-hydrox-ypro~yl) }trimeth~lene Chloride 24 A solution of 315 mg. (1.5 milliequiv.) of poly-[~methyl-(3-hydroxypropyl)imino~trimethylene bromide~ in 16 26 ml. of water is passed slowly through a column of 9 ml. of 27 Dowex l-X2 ion exchange resin (7.2 mmoles chloride ion), 28 and then water is passed through until the effluent gives 29 a negative test for chloride ion. The combined effluent is concentrated to dryness at 50~C. under reduced pressure . ,,.,.............. , ~ ~ . : -:.: . .
;

155~01 ~ ~ 5~ 7 1 yielding 230 mg. of poly-[~methyl-(3-'L~ydroxypropyl~imino}-2 trimethylene chloride].
3 In the preceding example, a polymer of Formula 4 III is synthesized in which Rl and R2 are each 3-hydroxy-propyl. The following three examples will demonstrate how 6 polymers of Formula III can be synthesized with Rl- 3-7 hydroxypropyl and R2=C~13. In these examples the Rl and R2 8 constitute from 5-95% and 95%-5~ respectively of the sum of 9 Rl -~ R2 and are distributed randomly along the polymer backbone.
11 EX~MPLE XXIX
12 Polymer of Formula III in which R = 3-hydroxypropyl and R2-13 CH ~RandomlY distributed in a 5:35 ratio) 14 A solution of 462 mg. (6 milliequiv.) of poly-[(methylimino)trimethylene] and 41 mg. (300 ~moles) of 3-bromo 16 propanol in 12 ml. of dimethylformami~e is heated at 75C.
17 for ~4 hours. The mixture is cooled and ~.9 g. (30 mmoles) 18 of methyl bromide is added. The reaction mixture is heated 19 at 50C. for three hours. The product is isolated by con-centration of the reaction mixture under reduced pressure 21 and is washed with ether and dried under reduced pressure.
22 Exchange of the bromide counter ion by chloride ion is 23 accomplished in the usual manner employing an ion-exchange 24 resin as described above.
EXAMPLE XXX
26 Polymer of Formula III in which R = 3-hydroxypropyl and R2 =
27 CH (Randomly distributed in a 50~50 ratio~

28 A solution of 213 mg. ~3 milliequiv.) of poly-29 [(methylimino)~rimeth~lene] and 209 mg. ~1.5 mmoles) of 3-broms-propanol is heated at 75C. for 24 hours. The reaction mix-31 ture is cooled and 1.5 g. of methyl bromide is added. The 32 reaction mixture is heated at 50C. for three hours and 33 worked up in t:he manner described above.

~' '' ~ ' ~L0'758'~7 1EXA~LE XXXI
2 Polymer of Formula III in which Rl = 3-hydroxypropyl and 3 R2 = CH3 _ ndomly~distributed in a 95:5 ratio?
4A solution o 142 mg. (2 miiliequiv.) of poly-5[(methylimino)trimethylenel and 264 mg. (1.9 mn~oles) of 3-6 bromopropanol is heated at 75C. for 16 hours. After the 7 mixture is cooled, 1 g. of methyl bromide is added and the 8 mixture is heated at 50C. for twelve hours. The reaction 9 mixture is worked up in the manner described above.
10EXP~LE XXXII
11 poly-[{Methyl-(3-methoxypropyl)imino~Eap~thl?r~9~5 12A solution of 284 mg. (4 milliequiv.) of poly-13[(methylimino)trimethylene] and 2.45 g. (16 mmoles) of 3-14 methoxypropyl bromide in 15 ml. of dimethylformamide is heated at 75C. for sixteen hours. The product is isolated 16 by filtration, washed with ether and dried under reduced 17 pressure. The product is dissolved in 25 ml. of water and 18 the bromide countex ion is exchanged for chloride ion by 19 ion-exchange as described above. In this manner, 450 mg.
of poly-[{methyl-(3-methoxypropyl)imino~trimethylene 21 chloride] is obtained.
22For the synthesis of polymers of Formula III in 23 which Rl and R2 are 3-methoxypropyl and methyl respectively ~4in ratios varying from 5:95 to 95:5, the procedure is essentially as described above in which the poly-[(methyl-26 imino)trimethylene] is reacted with a limiting amount of 27 3-methoxypropyl bromide and ~hen with an excess of methyl 28 bromide.

~7589L'7 1 EY~PLE XXXIII
2 Poly-[~lcthyl-(3-methylthiopropyl)imino3trimethylene 3 Cl~lori~e] _ _ _ _ _ 4 A solution of 426 mg. (6 milliequiv.) of poly-[(methylimino)trimethylene] and ~.06 g. of 3-methylthiopropyl 6 bromide in 15 ml. of dimethylformamide is heated at 75C.
7 for 24 hours. The product is isolated by filtration, taken 8 up in 30 ml. of water and passed through a column of 45 ml.
9 of Dowex~l-X2 ion-exchange resin (36 mmoles cllloride ion).
Concentration of the aqueous eluate yields 650 mg. of poly-11 E~methyl-(3-methylthiopropyl)imino3trimethylene chloride].
12 For the synthesis of polymers of Formula III in 13 which Rl and R2 are 3-methylthiopropyl and methyl respectively 14 in ratios varying from 5:95 to 95:5, the procedure is essen-tially as described abo~e in which the poly-[(methylimino)tri-16 methylene] is reacted with a limiting amount of 3-methylthio-17 propyl bromide and then with an exces, of methyl bromide.
18 E ~ ~LE XXXI~
19 Poly-[Methyl-(3-ammoniopropyl)imino~trimethylene Dichloride]
A solution of 568 mg. (8 milliequiv.) of poly-21 [(methylimino)trimethylene] and 8.6 g. (30 mmoles) of 3-phthal-22 imidopropyl bromide in 25 ml. of dimethylformamide is hea~ed 23 at 75C. for eighteen hours. The product is isolated by 24 filtration, suspended in 10 ml. of methanol and treated with 1 g. of anhydrous hydrazine at 50C. for three hours.
26 The mixture is concentrated at reduced pressure, acidified 27 with dilute HCl, triturated with ethex and isolated by 28 filtration. The product is taken up in water and passed 29 through a 45 ml. column of Dowex~l-X2 ion-exchange resin 155~0y 10'75~47 1 (36 mmoles chloride ion). Concentration of the aqueous 2 eluate yields poly-[~methyl-(3-ammoniopropyl)imino~tri-3 methylene dichloride].
4 Alternatively, a solution of 568 mg. (~ milli-equiv.) of poly-[(methylimino)trimethylene] and 6.3 g. (40 6 nmoles) of 1-bromo-3-chloropropane in 20 ml. of dimethyl-7 formamide is heated at 75C. for eighteen hours. The reac-8 tion mixture is concentrated under reduced pressure and 9 heated with 30 ml. of liquid ammonia at 50C. for five hours.
The ~lmonia is allowed to evapoxate, and the product is con-11 verted to the chloride-ion containing form by passage 12 through a 45 ml. column of Dowex~l-X2 ion-exchange resin 13 on the chloride ion cycle.
14 For the synthesis of polymers of Formula III in which Rl and R2 are 3-ammoniopropyl and methyl respectively 16 in ratios varying from 5:95 to 95:5, the procedure is 17 essentially as described above in which the ~oly-[(methyl-18 imino)trimethylene~ is reacted with a limiting amount of 19 either 3-phthalimidopropyl bro~ide or 1-bromo-3-chloropro-pane and then witll an excess of methyl bromice.

,.
22 Poly-[~Methyl-(3-methylammoniopropyl)imin ~ trimethylene 23 Dichloride]
.
24 A solution of 710 mg. (10 milliequiv.) of poly-~(methylimino)trimethylene ~ and 8 g. of 1-bromo-3-chloropropane 26 in 30 ml. of dimethylformamide is heated at 75C. for 16 27 hours. The mixture is concentrated under reduced pressure, 28 suspended in 10 ml. of methanol and treated with 3 g. of 29 methylamine at 50C. in a sealed tube. The reaction 1 30 mixture is concentrated under reduced pressure, taken up .

, .

: '' " ' .
. .

15540y 1~7S8~7 1 in water and passed through a 50 ml. column of Dowex~l-X2 2 ion exchange resin to yield the desired product.
3 For the synthesis of polymers of Formula III in 4 which Rl and R~ are 3~methylammoniopropyl and methyl respectively in ratios varying from 5:95 to 95:5, the 6 procedure is essentially the same as described above in 7 which the poly-[(methylimuno)trimethylene~ is first reacted 8 with a limiting amount of 1-bromo-3-chloropropane and then 9 with an excess of methyl bromide.
E~AMPLE XXXVI
11 Poly-~Methyl-(3-dimethylammoniopropyl)imino}trimethylene 12 Dichloride]
13 A solution of 710 mg. (10 milliequiv.) of poly-14 [(methylimino)trimethylene] and 7.9 g. of 1-bromo-3-chloro-propane in 35 ml. of dimethylformamide is heated at 75C.
16 for si~teen hours. The mixture is concentrated under re 17 duced pressure, suspended in 10 ml. of methanol and treated 18 with 2.3 g. (50 mmoles) of dimethylamine at 50C. in a sealed 19 tub~. The reaction mixture is concentrated under reduced pressure, taken up in water and passeu through a 50 ml.
21 column of Dowex l-X2 ion exchange resin (40 ml~loles of 22 chloride ion) yielding poly-[~methyl-(3-dimetllylammonio-23 propyl)imino~trimethylene dichloride].
24 Alternatively, a solution of 710 ms. (10 milli-equiv.) of pOly-[(methylimino~rim~thylene] in 35 ml. of di-26 methylformamide is treated with 6.6 g. (40 mmoles) of 3-di-27 methylaminopropyl bromide at 50C. for six hours. The 28 product is isolated by filtration, taken up in water and 29 passed through a 50 ml. column of Dowex~l-X2 ion-exchange resin (40 mmoles of chloride ion) yielding the 3-dimethyl-31 ammoniopropy:L analog above~

~ ,: , 15540`~
~S~

1For the synthesis of polymers of Fonnula III in 2 which Rl and R2 are 3-dimethylc~moniopropyl ~nd methyl 3respectively in ratios varying from 5:95 to 95:5 the proce-4 dure is essentially as described above in which the poly-l(methyl;mino)trimethylene] is treated with either a limiting 6 amount of 1-bromo-3-chloropropane or 3-dimethylaminopropyl 7 bromide and then with an e~cess of methyl bromide.

g Poly-[~Methyl-~3-trimethylammoniopropyl)imino}trimethylene Dibromide]
11A solution of 710 mg. (10 milliequiv.) of poly-12~(methylimino)trimethylene] and 10.4 g. (40 mmoles) of 3-bromo-13 propyltrimethylammonium bromide in 40 ml. of ~urified dimethyl-14 formamide is heated at 75C. for twelve hours. The product is isolated by filtration, washed with acetone and dried 16 under reduced pressure, yielding 1.8 g. of poly-[~methyl-17 (3-trimethylammoniopropyl)imino~trimethylene dibromide~.
18EX~-~LE XXXVIII
19 Poly-[~Methyl-(3-trimethylammoniopropyl)imino~trimethylene Dichloride]
21A solution of 1.66 g. (5 milliequiv.) of poly~
22 [~methyl-(3-trimethylammoniopropyl)imino~trimethylene di-23 bromide] in 85 ml. of water is passed slowly through a 24column containing 50 ml. (40 mmoles) of Dowex l-X2 resin on the chloride ion cycle. Water is then passed through until 26 no chloride ion can be detected in the eluate. Concentra-27 tion of the co~bined eluate to dryness at 50C. yields 1.1 g.
28 of poly-[~methyl-(3-trimethylammoniopropyl)i~in~ trimethylene 29 dichloride].
30For the synthesis of polymers of Formula III in 31 which Rl and R2 are 3-trimethylammoniopropyl and methyl 32xespectively in ratios varying from 5:95 to 95:5, the pro-~ 3~ -' , ' .

1~758~7 1 cedure is essentially as described abc)ve in Ex~mple XXXVII
2 in which the poly-[(methylimino)trimethylene] is reacted 3 with a limiting amount of 3-bromopropyltrimetllylammonium 4 bromide and then with an excess of methyl bromide.
E ~IPLE XXXIX
6 Poly-[~Methyl-(carboethoxymethyl)imino}trimethylene 7 Chlori e~
.. . . _ , _ 8 A solution of 1 g. (14 milliequiv.) of poly-g [(methylimino)trimethylene] and 8.8 g. (56 mmoles) of ethyl a-bromoacetate in 20 ml. of dimethylformamide is heated at 11 50C. for twelve hours. The mixture is diluted with five 12 volumes of ether and the product is isolated by filtra-13 tion. The product is taken up in water and passed through 14 a 75 ml. column of Dowex l-X2 ion-exchange resin (60 mmoles chloride ion) and the eluate is concentrated under reduced 16 pressure to yield poly-[~methyl-(carboethoxymethyl)imin~ -17 trimethylene chloride].

19 Poly-[~Methyl-(carboxylatomethyl?imino}trimet]lylen-e]
A solution of 500 mg. (7 milliequiv.) of ~oly-21 ~(methylimino)trimethylene] and 4.4 g. (28 mmoles) of ethyl 22 a-bromoacetate in 10 ml. of purified dimethylformamide is 23 heated at 50C. for 12 hours. The reaction mixture is con-24 centrated to dryness under reduced pressure, and the residue is treated with 28 ml. of lN sodium hydroxide overnight.
26 ~ext, 21 ml. of lN hydrochloric acid is added to the mixture 27 and the solution is desalted in an Amicon filter cell equip-28 ped with a UM2 Diaflo~UltrafilterD The solution is concen-29 trated to dryness at 50C. yielding 650 mg. of poly-~methyl-(carboxylatomethyl)imino~trimethylene].
:: :
.~

.~, ."~ .
. . .
'' :

155~0Y
-1~7~ 7 1 For the synthesis of polymers of Formula III in 2 which Rl and R2 are carboxylatomethyl and ~lethyl respectively 3in ratios ranging from 5:95 to 95:5 the procedure is essen-4 tially as described above in which poly-~(methylimino)tri-methylene] is reacted with a li~iting amount of ethyl-a-6 bromoacetate and then with an excess of methyl bromide.
7EXAMPL~ XLI
8 ~ lene Chloride g~ solution of 355 mg. (S milliequiv.) of poly-10[(methylimino)trimethylene] and 3.5 g. (25 mmoles) of 2-bromo-11 acetamide in 10 ml. of dimethylformamide is heated at 60C.
12 for 15 hours. The product is isolated by filtration, ta~en 13 up in water and passed through a 25 ml. column of Dowex 14 1-X2 ion exchange resin (20 mmoles chloride ion) yielding poly-[~methyl-(carbamylmethyl)imino~trimethylene chloride].
16For polymers of Formula III in which Rl and R2 17 are carbamylmethyl and methyl respectively in ratios varying 18from 95:5 to 5:95, the procedure is essentially as described 19 above in which the poly-[~methylimino)trimethylene3 is treated first with a limiting amount of 2-bromoacetanide and then 21 with an excess of methyl bromide.
22E ~ ~LE XLII
23 Poly-[J Methyl-(3-N2-methylcarbamidino?ropyl)imino~trimethylene 24 ~
25A solution of 710 mg. (10 milliequiv.) of poly-26[~methylimino)trimethylene] and 12.5 g. (90 mmoles) of 4-bromo-27 N -methyl-N-benzyloxycarbonylbutyramidine in 50 ml. of di-28 methylformamide is heated at 75C. for 16 hours. The mix-29 ture is concentrated under reduced pressure and the product is extracted into water. The aqueous solution is acidified .~ . .

~07~847 1 to p~ 3 with hydrochloric acid, hydrogenated over a 5% Pd/
2 carbon catalyst, filtered and passed throuyh a 100 ml. column 3 of Dowex~l-X2 ion-exchange resin (80 n~oles of chloride ion) 4 yielding the desired product containing the chloride counter ion.
6For compounds of Formula III in which Rl and R2 7 are 3-N -methylcarbamidinopropyl and methyl respectively in 8ratios of 95:5 to 5:95, the procedure descri~ed above is 9 employed in which the poly-[(methylimino)trimethylene~ is treated first with a limited quantity of 4-bromo N -methyl-11 N-benzyloxycarbonylbutyramidine and then with an excess of 12 methyl bromide.
13EX~MPLE XLIII
14 Poly-[~ ethyl-(3-guanidinopropyl)imino~trimethylene Chlori e Hydrochloride]
16A solution of 355 mg. (5 milliequiv.) of poly-17[(methy~mino)trimethylene] and 5.6 g. (25 mmoles) of Nl-3-18 bromopropyl-N3-nitroguanidine in 15 ml. of dimethylformamide 19 is heated at 75C. for 16 hours. The mixture is concen-trated at reduced pressure and the product is extracted 21 into water. The aqueous solution is acidified to pH 3 with 22 hydrochloric acid and hydrogenated in the presence of 100 23 mg. of activated platinum. The solution is filtered and 24 passed through a 50 ml. column of Dowex~l-X2 ion-exchange resin (40 mmoles of chloride ion) yielding the desired 26 product containing the chloride counter ion.
27For compounds of Formula III in which Rl and R2 28 are 3-guanidinopropyl and methyl respectively in ratios 29varying from 95:5 to 5:95, the procedure described above is applied in which the poly-[ (methylimino)trimethylene3 is ; - 39 -: - , , ~.

15540~
, ~0~i8~

1 first treated with a limiting c~mount of N -3-bromopropyl-2 N3-nitroguanidine and then with an excess of methyl bromide.

4 Poly-[~Methyl-(2-oxopropyl)imi ~ hylene Chloride]
A solution of 355 mg. (5 milliequiv.) of poly-6 [(methylimino)trimethylene] and 2.3 g. (25 m~oles) of 7 chloropropanone-2 is heated at: 50C. ~or 16 hours. The 8 product is isolated by filtration, triturated with ether 9 and dried under reduced pressure.
For polymers of Formula III in which Rl and R2 11 are 2-oxopropyl and methyl respectively in ratios varying 12 from 95:5 to 5:95, the procedure described above is followed 13 in which the poly-~(methylimino)trimcthylene] is treated first 14 with a limiting amount of chloropropanone-2 and then with an excess of methyl bromide. Treatment of the product with -16 Dowex~l-X2 on the chloride ion cycle gives th~ product con-17 taining the chloride ion exclusively.
18 EXAMPLE ~LV
19 Poly-[~M~ l-(benzyl)imino~trimethylene Chloride]
A solution of 710 mg. (10 milliequiv.) of poly-21 [(methylimino)trimethylene] and 6.8 g. (40 mmoles) of benzyl 22 bromide in 15 ml. of dimethylformamide is heated at 50C.
23 for 16 hours. The product is isolated by concentration of 24 the reaction mixture under reduced pressure and extraction into water. The aqueous solution is passed through a 25 ml.
26 column of Dowex~l-X2 ion exchange resin (40 mmoles of 27 chloride ion) yielding the desired product containing the 28 chloride counter ion.

. 40 -~07S~3~7 For polymers of Formula III in whic~l Rl and R2 2 are benzyl and methyl respectively, the procedure described 3 above is followed in which the poly-[(methylimino)trimethylene]
4 is first reacted with a limited amount of benzyl bromide and then an excess of methyl bromide.
6 E,YAMPLE XLVI
7 Poly-~Methyl=(l-propen-3-y-l mino~trimethYlelle-chloride]
8 A solution of 426 mg. (6 milliequiv.) of poly-g [(methy~l~no)trimethylene] and 3.7 g. (30 mmoles) of 3-bromo-propene-l (allyl bromide) in 12 ml. of dimethylformamide is 11 heated at 50C. for 16 hours. The product is isolated by 12 filtration and dissolved in water. The aqueous solution is 13 passed through a 40 ml. column of Dowex~l-X2 ion exchange 14 resin (32 ~moles of chloride ion) and the eluate is concen-trated under reduced pressure yielding the desired product 16 containing the chloride counter ion.
17 For compounds of Formula III in which Rl and R2 18 are 1-propen-3-yl and methyl respectively in ratios vary-19 ing from 95~5 to 5:95, the procedure is similar to that described above in which the poly-[(methylimino)trimethylene]
21 is reacted with a limiting quantity of 3-bro~iopropene-1 and 22 then an excess of methyl bromide.
23 EX~PLE XLVII
24 Poly-[~Methyl~ propyn-3-yl)imin~ trimethylene Chloride]
A solution of 710 mg. (10 milliequiv.) of poly-26 [(methylimino)trimethylene] and 3.6 g. (30 mmoles) of 3-27 bromopropyne-l (propargyl bromide) in 12 ml. of dimethyl-28 formamide is heated at 50C. for 16 hours. Tlle product is 29 isolated by filtration, dissolved in ~Jater anc' passed .
, . .

155~0`~
-S8~7 l throu~h a 40 ml. column of Dowex~l-X2 ion exchange resin 2 (32 mmoles of chloride ion) yielding the desired product 3 containing the chloride counter ion.
4 As for previous ex~nples, polymers of Formula III
in which Rl= l-propyn-3-yl and R2= C~13 in ratios ranging 6 from 5:95 to 95:5 are synthesized by first treating the 7 poly-[~ethylimino)trimethylene] with a limiting amount of 8 propargyl bromide and then with an excess of methyl bromide.

Poly-[~Methyl-(2,2,2-trifluoroethyl)imino~trir~ethylene ll Chloride]
~ . .
12 A solution of 355 mg. (5 milliequiv.) of poly-13 ~(methylimino)trimethylene~ and 6.2 g. (22 mmoles) of 2,2,2-14 trifluoroethyl trichloromethylsulfonate in 15 ml. of dimethyl-formamide is heated at 50C. for 16 hours. The reaction 16 mixture is diluted with ether and the product is isolated 17 by filtration. The product is taXen up in water and passed 18 through a 25 ml. column of Dowex~l-X2 ion exchange resin l9 ~20 mmoles chloride ion) and the eluate is concentrated under reduced pressure yielding the desired product contain-21 ing the chloride counter ion. -22 For pol~mers of Formula III in which Rl and R2 23 are 2,2,2-trifluoroethyl and methyl respectively in ratios 24 varying from 95:5 to 5:95, the procedures described above are employed in which the poly-[~methylimino)trimethylene] is 26 first treated with a limiting quantity of 2,2,2-trifluoro-27 ethyl trichloromethylsulfonate and then with an excess of 28 methyl bromide.

~ ' ~ ,,, .:

1 5540'~
10'75~7 I~J .YAMP F._XI,I X
2 Poly- rf Methyl- ( l-a -D-glucopyranosyl) imino}trirlethylene 3 Chloride]
_ _ _ _ _ ___ _ ___ 4 A solution of 535 mg~ 55 milliequiv.) of poly-[(methylimino)trimethylene] and 10.3 g. (25 m~oles) of 6 tetra-O-acetyl-a-D-glucopyranosyl bromide in Z5 ml. of di-7 methylformamide is heated at 50C. for 16 hours. The pro-8 duct is isolated by dilution with ether followed by 9 filtration. The product is taken up in 5 ml. of water and 2 ml. of 10% hydrobromic acid is adde~. After being 11 allowed to stand overnight, the solution is diluted to a 12 volume of 100 ml. with water and placed in an Amicon filter 13 cell containing a UM-2 Diaflo~Ultrafilter. ~fter 800 ml.
14 of filtrate is collected, the retentate is concentrated to a 50 ml. volume and passed through a 25 ml. column of Dowex~
16 1-X2 ion exchange resin (20 mmoles of chloride ion). Concen-17 tration of the eluate yields the desired analog containing 18 the chloride counter ion.
19 For compounds of Formula III in which R1 and R2 are l-a-D-glucopyranosyl and methyl respectivcly in ratios 21 varying from 9~:5 to 5:95, the procedure described above is 22 followed in which the poly-[(methylimino)trimethylene] is 23 treated first with a limiting quantity of tetra-O-acetyl-a-24 P -glucopyranosyl bromide and then an excess of methyl 2 5 bromide.
26 The procedures described in ~xamples XXVII through 27 XLIX are equally applicable for conversions of poly-[(methyl-28 imino)ethylene] to the corresponding quaternary analogs and 29 are followed using the corresponding milliequivalents of poly-[(methylimino)ethylene] in place of the poly-[(methyl-31 imino)trimethylene~ as shown in Example L.

~75~3~7 EXAMPLE L

Poly- ~Methyl-(2-trimethylammonioethyl)imino}ethylene Dibromid ~
A solution of 570 mg. (10 milliequiv.) oE poly-~methylimino)ethylen ~ ancl 9.9 g. (40 mmoles) of 2-bromo-ethyltrimethylammonium bromide in 40 ml. of dimethylformamide is heated a-t 75C. for 12 hours. Af-ter being cooled, -the reaction mixture is dilu-ted with five volumes of ether, and the product is isolated by filtration and dried under reduced pressure.
Effective lowering of choles-terol 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 supple-tary 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 which can be prepared and are preferably sweetened or .
.

7S8~7 flavored. Although not entirely desirable, -the polymers can be mixed in various vehicles such as safflower or corn 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 bedtime. This regimen provides for maximum resin contact time duriny 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 clo-fibrate and halofenate, which salts are useful in cardio-vascular disease therapy. The following examples are illustrative 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 2Q 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 tocamphyl florantyrone; taurine; and glycine; hypocholesteremic agents such as nicotinic acid; the D-isomer of 3,3',5-triiodothyronine; thyroxine-like compounds 3Q such as sodium L-thyroxin and sodium D-thyroxine; triiodo-thyropropionic acid; nafoxidine hydrochloride, 5-methyl-, : ' ' .

pyrazole-3-carboxylic acid ancl 3-methyl-5-isoxazolecarboxylic acid; fecal softeners such as poloxalkol and dioc-tyl sodium sulfosuccinate; 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- ~dimethylimino)ethylene chlorid ~ there can be substituted therefor poly- ~2-hydroxy-ethyl)methyliminoethylene chlorid ~ 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- rdimethyl-imino)ethylene chlorid ~ containing 1% by weight of lactose as described above is filled in-to the appropriate size hard gelatin capsules.
Alternatively, a dry filled capsule can be prepared from the following components:

poly- ~ (trimethylammonioethyl)methylimino}-ethylene chlorid ~ 300 mg.
corn starch 150 mg.
30 Cab-o-sil~ (anhydrous silica) 5 mg.

.~.... .
.

Dry filled capsules can likewise be prepared usiny any of the other novel polymers set forth in this specifi-cation. If capsules of lower potency are to be prepared, the capsule size can be decreased or addi-tional corn starch or other diluent employed. When using smaller amounts of active ingredien-t 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 chlorid ~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:

; 20 poly- ~dimethylimino)ethylene chlorid ~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 cellu-lose acid phthalates applied by techniques well known and accepted.
'` ` '~

, . ~ ~ . , 1~7S8~7 1 In place of the poly-[tdimethy~ rloethylene 2 chloride], there may be substitutcd any of tllc polymers 3 of our invention.
4 Other binding agents may bc used in place of sucrose, such as dextrose, lactose, methyl cellulose, 6 natural and synthetic gums, and the like. Talc can replace the calcium or magnesium stearate. P variety of ~ readily available non-toxic anti-cal;ing agents may be sub-g stituted for the colloidal silica.
Other lubricants, diluents, binclers, coloring 11 agents, flavoring agents and disintegrators can be used 12 as are known in the art employing wet or dry granulation 13 techniques, direct compression, spray drying and the like.
14 If desired, a chewable tablet can be prepared from preferably microencapsulated polymer particles by dry granu-16 lation as follows:
17 In Each Tablet 18 mieroencapsulated poly-[(dimethyl-19 imino)ethylene chloride] 750 mg.
mannitol 300 mg.
21 sodium saccharine (or other artificial 22 sweetener) 2 mg.
23 oil of p~eppermint 1 ~g.
24 Carbowax~4000 15 mg.
microcrystalline cellulose 100 mg.
26 The polymers of this invention are additionally 27 espeeially useful throughout their molecular weight range 28 when employed as agents for the flocculation of colloidal 29 particles in liquids such as, for example, as fresh and waste water. They can also be used as retention aids when 31 added to papex furnish during the papermakir.g operation.
32 Furthermore, the polymers are useful as anti~acterial and 33 antistatic agents and as the latter, can be employed in the 55~0Y
~0~7S8~7 1 treatment of cotton, wool, and synthetic fibers. These 2 polymers can also be used as ~abric softeners, and dye 3 assists, especially for the binding o~ anionic type dyes.
~ In addition, they can be used as viscosity builders, as S well as adding antibacterial properties to non-ionic and 6 cationic detergent formulations, cosmetics, hair sprays 7 and similar applications. W~en so used, the polymers of 8 this invention are employed in a like quantity and in an 9 analogous manner to conventional kno~m materials used for such purposes.
ll When employed as a clarifying or flocculating 12 agent, the polymers of this invention are preferably dis-13 solved or dispersed in an aqueous medium and added to the 14 water to be treated in an amount of from 0.5 lb. to 2 lb.
of polymer for each l,000 gallons of water to be treated.
16 In general, the polymers of this invention have 17 a molecular weight of from 300 to 50,000 and more. 11hile 18 suitable for use as flocculating agents and the like, those 19 polymer molecules having molecular weights below 1,500 are not suitable as bile acid binding agents, and such polymer 21 molecules can be separated from the higher weight molecules 22 by known methods.
23 These polymers are administered orally in an 24 effective bile acid binding dose. For lowering blood serum cholesterol levels, generally a single or multiple 26 dose of from about O.l to 5.0 grams is suitable altnough 27 doses in excess of lO grams can be given where indicated~
28 Such doses are also effective in relieving symptoms of 29 biliary pruritus. Administration can be in a variety of forms, such as a suspension, in an a~ueous solution, as :.
;' ~ , ` .

S~7 1 a caewable or a coated tablet, or in a capsule, and can 2 be continued for an extended course of treatment.
3 Generally, medication is on a daily basis with each 4 day's dose taken in divided portions, preferably with S meals.
6 For control of hypercholesterolemia, the 7 particular individual dosage, given variances in 8 metabolism and diet, is preferably arrived at through g an initial determination and continued monitoring of blood serum cholesterol levels. Thus, a moderate dosage 11 might be employed initially, and increased until the 12 desired blood serum cholesterol level is achieved and 13 maintained. For an initial dose, pending such individual 14 adjustment, from 2.5 to 100 mg./kg. of body weight per day is satIsfactory.
16 One skilled ;`n the art will appreciate that Rl, 17 R2, R3 and R4 when ammonioloweralkyl, loweralkylammoniolower 18 alkyl, diloweralkylammonioloweralkyl can also be in the form 19 of the free a~ine, n~mely, aminoloweralkyl, loweralkylami~o-loweralkyl and diloweralkylaminoloweralkyl, respectively.

Claims (16)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. Process for preparing poly- (methyl-(3-tri-methylammoniopropyl)imino}trimethylene dihalide) or poly-(methyl-(3-hydroxypropyl)imino}trimethylene halide) which comprises (a) reacting poly- (methylimino)trimethylen) with 3-bromo-propyltrimethylammonium halide to form the poly- (methyl-(3- trimethlammoniopropyl)imino) trimelythylene dihalide) and when a different dihalide is desired reacting the latter compound with an ion-exchange resin on a different halide cycle, or (b) reacting poly- (methylimino)trimethylene) with 3-halo-propanol to form the poly- (methyl-(3-hydroxypropyl)imino}-trimethylene halide) and when a different halide is desired reacting the latter with an ion-exchange resin on a different halide cycle.

2. Process for preparing poly- (methyl-(3-tri-methylammoniopropyl)imino}trimethylene dihalide) which comprises reacting poly- (methylimino)trimethylene) with 3-bromo-propyltrimethylammonium halide and isolating the poly-(methyl-(3-trimethylammoniopropyl)imino}trimethylene) dihalide) thus formed.

3. The process of Claim 2, wherein the poly-(methyl-(3-trimethylammoniopropyl)imino}trimethylene dihalide) obtained is reacted with an ion-exchange resin on a different halide cycle.

4. Process for preparing poly- (methyl-(3-tri-methylammoniopropyl)imino}trimethylene dibromide) which comprises reacting poly- (methylimino)trimethylene) with 3-bromo-propyltrimethylammonium bromide and isolating the poly-(methyl-(3-trimethylammoniopropyl)imino}trimethylene dibromide) thus formed.

5. The process of Claim 4, wherein the poly-(methyl-(3-trimethylammoniopropyl)imino}trimethylene dibromide) obtained is reacted with an ion-exchange resin on a chloride ion cycle to form the poly- (methyl-(3-trimethyl-ammoniopropyl)imino}trimethylene dichloride).

6. Process for preparing poly- (methyl-(3-hydroxy-propyl)imino}trimethylene halide) which comprises reacting poly- (methylimino)trimethylene) with 3-halo-propanol to form the poly- (methyl-(3-hydroxypropyl)imino}trimethylene halide).

7. The process of Claim 6, wherein the poly-(methyl-(3-hydroxypropyl)imino}trimethylene halide) obtained is reacted with an ion-exchange resin on a different halide cycle.

8. Process for preparing poly- (methyl-3-(hydroxy-propyl)imino}trimethylene bromide) which comprises reacting poly- (methylimino)trimethylene) with 3-bromo-propanol and isolating the poly- (methyl-3-(hydroxypropyl)imino}tri-methylene bromide) thus obtained.

9. The process of Claim 8, wherein the poly-(methyl-3-(hydroxypropyl)imino}trimethylene bromide) obtained is reacted with an ion-exchange resin on a chloride.

10. Poly- (methyl-(3-trimethylammoniopropyl)imino}-trimethylene dihalide) or poly- (methyl-3-(hydroxypropyl)-imino}trimethylene halide), when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

11. Poly- (methyl-(3-trimethylammoniopropyl)imino}-trimethylene dihalide), when prepared by the process defined in Claim 2 or 3 or by an obvious chemical equivalent.

12. Poly- (methyl-(3-trimethylammoniopropyl)imino}-trimethylene dibromide), when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

13. Poly- (methyl-(3-trimethylammoniopropyl)imino}-trimethylene dichloride), when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

14. Poly- (methyl-(3-hydroxypropyl)imino}tri-methylene halide), when prepared by the process defined in Claim 6 or 7 or by an obvious chemical equivalent.

15. Poly- (methyl-(3-hydroxypropyl)imino}tri-methylene bromide), when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.

16. Poly- (methyl-(3-hydroxypropyl)imino}tri-methylene chloride), when prepared by the process defined in Claim 9 or by an obvious chemical equivalent.