CN1189168A

CN1189168A - Hydrophobic heteroatom-containing sequestrant for cholesterol depletion

Info

Publication number: CN1189168A
Application number: CN96194613A
Authority: CN
Inventors: 亨利·W·曼德维尔三世; 史蒂芬·雷多·霍尔姆斯－法利; 约翰·S·皮特森
Original assignee: Geltex Pharmaceuticals Inc
Current assignee: Geltex Pharmaceuticals Inc
Priority date: 1995-06-06
Filing date: 1996-06-06
Publication date: 1998-07-29

Abstract

The present invention relates to a poly(allylamine) polymer and, more generally, a hydrocarbon amine polymer. Preferably, these polymers are crosslinked. The present invention also relates to methods of forming these polymers and methods for their use. Further, the present invention relates to alkylating agents that can be employed to form the polymers and to methods for forming the alkylating agents. Generally, the polymer sequestrant includes a substituent bound to an amine of the polymer. The substituent includes a quaternary amine-containing moiety having one, two or three terminal hydrophobic substituents. A method of preparing quaternary amine-containing alkylating agents includes reacting an unsymmetrical dihalide with a tertiary amine having at least one hydrophobic substituent. A method for binding bile salts of bile acids in a mammal includes orally administering to the mammal a therapeutically-effective amount of the polymer sequestrant.

Description

Hydrophobic heteroatom-containing chelators for cholesterol scavenging

Related application of the invention

This application is a partial continuation of U.S. application No. 08/469,659 (App. No.: 6/1995), which is a partial continuation of U.S. application No. 08/258,431 (App. No.: 6/10/1994) and U.S. application No. 08/332,096 (App. No.: 10/31/1994), which are all incorporated herein by reference.

Background of the invention

Bile acid salts act as detergents to solubilize and thereby help digest fat in food. Bile acids are produced from cholesterol and, therefore, removal of bile acids will result in a decrease in cholesterol. After digestion bile acids are either (passively) absorbed in the jejunum or reabsorbed by active transport in the ilium. Bile acid that is not reabsorbed is lost.

Reabsorption of bile acids from the intestinal tract preserves lipoprotein cholesterol in the bloodstream. In contrast, blood cholesterol concentrations may be reduced due to reduced reabsorption of bile acids.

One method of reducing the amount of bile acid reabsorption is to orally administer a compound that is capable of conjugating bile acids without itself being absorbed. These chelated bile acids are eventually excreted.

However, many bile acid sequestrants do not bind conjugated primary bile acids, e.g., do not bind conjugated bile acids well to prevent reabsorption of a major portion. In addition, the volume of chelating agent that can be digested is limited. As a result, the efficiency of many chelators in lowering blood cholesterol levels is also limited.

Moreover, the synthesis of many chelating agents can also be limited by the reaction yield and expense of preparing suitable precursors. For example, alkylating agents used to effect polymer modification can be difficult to prepare. In addition, the ability of the alkylating agent to react with the polymer may also limit the efficiency of the resulting chelating agent.

Thus, there is a need for a chelating agent and a method that overcomes or minimizes the above-mentioned difficulties.

Summary of the invention

This invention relates to poly (allylamine) polymers and, more generally, to hydrocarbon amine polymers. These polymers are preferably crosslinked. The invention also relates to methods of making and using these polymers. In addition, the present invention relates to alkylating agents useful in the preparation of these polymers and to processes for preparing alkylating agents.

In one aspect, the poly (allylamine) polymer is crosslinked and contains substituents attached to the amine of the polymer. The substituents include quaternary amine-containing moieties wherein the nitrogen of the quaternary amine moiety is linked to the amine of the polymer through an alkylene group having 3 or more carbon atoms, and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having 6 to about 24 carbon atoms, and the remaining terminal substituents are each independently an alkyl group having 1 to about 5 carbon atoms.

A method of making a crosslinked poly (allylamine) polymer comprising reacting a crosslinked poly (allylamine) with a quaternary amine-containing compound having the formula,

wherein,

r represents alkyl, at least one of which has 6 to about 24 carbon atoms and the remainder each having 1 to 5 carbon atoms,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

In another aspect, the invention relates to a hydrocarbyl amine polymer having a substituent attached to the amine of the polymer, the substituent comprising a quaternary amine-containing moiety wherein the nitrogen of said quaternary amine moiety is attached to the amine of the polymer by an alkylene group having 3 or more carbon atoms, and wherein at least two of the three terminal substituents of the quaternary amine are hydrophobic alkyl groups having 6 to about 24 carbon atoms and the remaining one terminal substituent is an alkyl group having 1 to about 5 carbon atoms.

The process for preparing the crosslinked hydrocarbon amine polymer of the present invention comprises polymerizing the crosslinked hydrocarbon amine polymerA step of reacting with a quaternary ammonium compound having the following formula,

wherein,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

The methods of using the poly (allylamine) polymers and hydrocarbon amine polymers of the invention include orally administering to a mammal a therapeutic amount of these polymers to bind bile acids, lower blood cholesterol, treat atherosclerosis, treat hypercholesterolemia, or lower blood lipid levels in a mammal. In another aspect, the present invention relates to quaternary ammonium compounds having the structure,

wherein,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

A method of preparing a quaternary ammonium compound comprises reacting a tertiary amine having the formula:

wherein,

a step of reacting with an asymmetric dihalide having the formula,

X¹--(CH₂)_n--X²

wherein,

X¹is a chlorine-containing compound having a chlorine-containing group,

X²is bromine, and

n is an integer of 3 or more.

The present invention has many advantages. For example, the poly (allylamine) and hydrocarbon amine polymer sequestrants of the present invention bind to conjugated bile acids, including primary bile acids, which would otherwise be actively transported for reabsorption. One possible explanation for the improved performance of the polymeric chelants of the present invention in binding bile acids is their ability to form hydrogen and ionic bonds with bile acids. The hydrogen bond may be formed by a secondary amine moiety of the polymer, while the ionic bond may be formed by a quaternary amine substituent. Furthermore, the external or terminal distribution of the hydrophobic portion of the polymeric chelant in relation to the backbone of the polymer and to the secondary and quaternary amine portions of the polymer contributes to a significant increase in the efficiency of each given dose of chelant. In addition, the presence of two or more hydrophobic alkyl groups as terminal substituents provides more sites for hydrophobic binding of bile salts.

The process for the preparation of the polymeric chelant of the present invention also includes several advantages. For example, alkylation of the amine moiety of a hydrocarbon amine polymer, such as a poly (allylamine) polymer, with a quaternary amine can be achieved by reacting with an amine moiety on a carbon atom-bearing leaving group that removes at least three carbon atoms from the center of the quaternary amine. In addition, it is believed that the incorporation of quaternary amines into hydrocarbon amine polymers, especially poly (allylamine) polymers, using alkylene groups having at least three carbon atoms, results in improved performance of the resulting chelants.

The use of asymmetric dihalides in the preparation of quaternary amine-containing alkylating agents of the present invention can increase the yield and purity of the desired product. Since the halogen in the asymmetric dihalide is not equivalent in reactivity, the reaction of the carbon atom bearing the more reactive halogen is almost specific, and therefore it produces a relatively pure compound in good yield. This relatively pure quaternary amine-containing alkylating agent can then be used to alkylate the amine nitrogen atoms of the hydrocarbon amine polymer backbone. Detailed description of the invention

The features and other aspects of the present invention will now be more particularly described and claimed in the appended claims. It should be understood that the specific examples, which are provided to illustrate the invention, are not limiting of the invention. The essential features of the invention can be used in a variety of situations without departing from the scope of the invention.

The term "hydrocarbon amine polymer" as used herein refers to a polymer consisting essentially of carbon, hydrogen and nitrogen. Preferred hydrocarbon amine polymers are crosslinked. More preferred hydrocarbon amine polymers are poly (allylamine) polymers. The most preferred hydrocarbon amine polymers are crosslinked poly (allylamine) polymers. Other examples of suitable hydrocarbon amine polymers include poly (vinyl amine) and poly (aziridine) polymers.

The hydrocarbon amine polymer chelants of the present invention contain a substituent attached to the amine of the polymer. The substituents include quaternary ammonium moieties wherein the nitrogen of the quaternary ammonium moiety is linked to the amine on the polymer backbone through an alkylene group having 3 or more carbon atoms. Furthermore, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having from 6 to about 24 carbon atoms, and the remaining terminal substituents are each independently an alkyl group having from 1 to about 5 carbon atoms.

The term "terminal substituent" of a quaternary amine as used herein refers to any of the three substituents on the nitrogen atom of the quaternary amine and is not the carbon chain between the amine on the polymer backbone and the amine of the quaternary ammonium center.

The term "hydrophobic alkyl" as used herein refers to an alkyl group having from 6 to about 24 carbon atoms and terminating in a hydrophobic moiety. For example, the hydrophobic alkyl group may be an aliphatic, aromatic, branched or cyclic carbon chain. The hydrophobic substituent does not include an alkylene group between a nitrogen on the amine polymer backbone and a nitrogen of the quaternary ammonium center.

In one embodiment, the hydrocarbon amine polymer is a crosslinked poly (allylamine) polymer and contains substituents attached to the amine of the polymer. The substituents include quaternary amine-containing moieties wherein the nitrogen of said quaternary amine moiety is linked to the amine of the polymer through an alkylene group having 3 or more carbon atoms, and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having 6 to about 24 carbon atoms, and the remaining terminal substituents are each independently an alkyl group having 1 to about 5 carbon atoms.

Preferred examples include crosslinked poly (allylamine) polymers wherein the alkylene group is three carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which may be octyl, decyl or dodecyl, and the remaining terminal substituents are methyl.

Other preferred examples include crosslinked poly (allylamine) polymers wherein the alkylene group is four carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which may be octyl, decyl or dodecyl, and the remaining terminal substituents are methyl.

Other preferred examples include crosslinked poly (allylamine) polymers wherein the alkylene group is five carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which may be octyl, decyl or dodecyl, and the remaining terminal substituents are methyl.

Still other preferred examples include crosslinked poly (allylamine) polymers wherein the alkylene group is six carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which may be octyl, decyl or dodecyl, and the remaining terminal substituents are methyl.

In one aspect, the poly (allylamine) polymers of the invention have the following general structure,

wherein,

n is an integer of 3 or more, and

r represents alkyl groups, at least one of which has 6 to about 24 carbon atoms and the others each having 1 to 5 carbon atoms.

wherein,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

Preferred examples of cross-linked poly (allylamine) s prepared by this method include cross-linked poly (allylamine) polymers in which the alkylene group is three carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which may be octyl, decyl or dodecyl, and the remaining terminal substituents are methyl.

Other preferred examples of cross-linked poly (allylamine) s prepared by this method include cross-linked poly (allylamine) polymers in which the alkylene group is four carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which may be octyl, decyl or dodecyl, and the remaining terminal substituents are methyl.

Other preferred examples of cross-linked poly (allylamine) s prepared in this way include cross-linked poly (allylamine) polymers in which the alkylene group is five carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which may be octyl, decyl or dodecyl, and the remaining terminal substituents are methyl.

Some other preferred examples of cross-linked poly (allylamine) s prepared by this method include cross-linked poly (allylamine) polymers in which the alkylene group is six carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which may be octyl, decyl or dodecyl, and the remaining terminal substituents are methyl.

In another aspect, the present invention relates to hydrocarbon amine polymers containing one substituent attached to the amine of the polymer. The substituents include quaternary amine moieties wherein the nitrogen atom of said quaternary amine moiety is linked to the amine on the polymer backbone through an alkylene group of 3 or more carbon atoms, and wherein at least two or all three of the three terminal substituents of the quaternary amine are each a hydrophobic alkyl group of 6 to about 24 carbon atoms. In the case where two or three terminal substituents of the quaternary amine are each hydrophobic alkyl groups, the remaining terminal substituents are alkyl groups having from 1 to about 5 carbon atoms. In a preferred embodiment the hydrocarbon amine polymer is crosslinked.

The method of making the crosslinked hydrocarbon amine polymer of the present invention includes the step of reacting the crosslinked hydrocarbon amine polymer with a quaternary ammonium compound having the formula,

wherein,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

Preferred examples of crosslinked hydrocarbon amine polymers prepared by this method include poly (vinyl amine), poly (allyl amine), and poly (aziridine) polymers.

The methods of using the poly (allylamine) polymers and hydrocarbon amine polymers of the invention include orally administering to a mammal a therapeutic amount of these polymers to bind bile acids, lower blood cholesterol, treat atherosclerosis, treat hypercholesterolemia, or lower blood lipid levels in a mammal. Typically, the therapeutic amount of hydrocarbon amine polymer and poly (allylamine) polymer is about 0.1 to about 20 grams per day.

In one aspect, the present method is a method of binding bile salts of a mammal comprising the step of orally administering to the mammal a therapeutic amount of a hydrocarbon amine polymer of the present invention. In another aspect, the present method is a method of binding bile salts of a mammal comprising the step of orally administering to the mammal a therapeutic amount of a poly (allylamine) polymer of the present invention.

In another aspect, the present method is a method of lowering blood cholesterol in a mammal comprising the step of administering to the mammal a therapeutic amount of a hydrocarbon amine polymer of the present invention, preferably a cross-linked poly (allylamine) polymer. In yet another aspect, the invention includes a method of treating atherosclerosis in a mammal comprising the step of administering to the mammal a therapeutic amount of a hydrocarbon amine polymer of the invention, preferably a cross-linked poly (allylamine) polymer. In yet another aspect, the present method is a method of treating hypercholesterolemia in a mammal comprising the step of administering to the mammal a therapeutic amount of a hydrocarbon amine polymer, preferably a crosslinked poly (allylamine) polymer, of the present invention.

Another aspect of the present invention is a method of reducing blood lipid levels in a mammal comprising orally administering to the mammal a polymer of the present invention to tightly sequester conjugated bile acids secreted by the mammal, whereby a major portion of the conjugated bile acids are excreted by the mammal, thereby accelerating lipid metabolism and thereby reducing blood lipid levels in the mammal. In a preferred example, the chelated primary bile acid includes conjugated primary bile acids, such as conjugated cholic acid and conjugated chenocholic acid.

The hydrocarbon amine polymers and poly (allylamine) polymers of the invention are particularly suitable for binding conjugated primary bile acids such as glycocholic acid and glycochenocholic acid in the body of a mammal by oral administration of the polymer. A form particularly suitable for oral administration of hydrocarbon amine polymers and poly (allylamine) polymers is one that forms a gel in the stomach of a patient.

Preferred amine polymers of the present invention can be prepared by any suitable method, examples of which are as follows:

1. one method is to prepare a homopolymer by polymerizing amine monomers. Examples of such processes include the polymerization of allylamine, aziridine, vinylamine, 1, 2-diaminoethylene, aminopropylacrylate or p-aminomethylstyrene to produce their respective homopolymers.

2. Another approach is to copolymerize the amine monomer with one or more other monomers. Such other monomers include amine monomers, such as those listed above, and non-amine monomers such as acrylamide, styrene, divinylbenzene, vinyl alcohol or vinyl chloride. Examples include copoly (allylamine/acrylamide), copoly (vinylamine/allylamine), and copoly (allylamine/divinylbenzene).

3. Another method is to polymerize non-amine monomers to produce homopolymers, which are then chemically modified to form amine polymers. Examples of such processes include the polymerization of vinyl formamide, vinyl acetamide, vinyl chloride, vinyl bromide, allyl chloride, allyl bromide, acrylamide or acrylonitrile to form their respective homopolymers. Each homopolymer is then chemically modified by hydrolysis, nucleophilic substitution or reduction to form an amine polymer. Thus, the first four homopolymers above become poly (vinylamine) and the last four become poly (allylamine). It will be appreciated that not all of the initial non-amine monomers need be chemically modified to yield amine polymers containing some initial non-amine monomers in a non-amine state.

4. A fourth method is to copolymerize the non-amine monomer with one or more other monomers. The other monomers include amine monomers, such as those listed in the first method, and non-amine monomers, such as those listed in the third method. The resulting copolymer was then chemically modified to prepare the amine polymers listed in the third method. Examples include the copolymerization of acrylamide with styrene followed by reduction to produce the copolymer (allylamine/styrene); copolymerizing acrylonitrile with vinylformamide, followed by reduction and hydrolysis reactions, to form a copoly (allylamine/vinylamine); and copolymerizing acrylonitrile with allylamine followed by reduction to form poly (allylamine). It will be appreciated that not all of the initial non-amine monomers need be chemically modified to yield amine polymers containing some initial non-amine monomers in a non-amine state.

5. A fifth method involves the preparation of amine polymers by a condensation mechanism. Examples of such processes include the reaction of diethylenetriamine with epichlorohydrin, 1, 3-dibromopropane with ethylenediamine, spermine with 1, 4-butanediol diglycidyl ether, or tris (2-aminoethyl) amine with 1, 10-dibromodecane.

Each of these amine polymers generally has a molecular weight greater than about 2,000. Examples of suitable resulting hydrocarbon amine polymers include poly (vinyl amine), poly (allyl amine), and poly (aziridine) polymers. Preferred hydrocarbon amine polymers are poly (allylamine) polymers.

Preferred hydrocarbon amine polymers are crosslinked, for example, by reacting the polymer with a suitable crosslinking agent. Examples of suitable crosslinking agents include acryloyl chloride, epichlorohydrin, butanediol glycidyl ether, ethylene glycol glycidyl ether, dimethyl succinate, and the like. Epichlorohydrin is a preferred crosslinking agent. Generally, the amount of crosslinking agent used to react with the hydrocarbon amine polymer is sufficient to allow about 0.5-20% of the sites available for reaction with the crosslinking agent to occur. In a preferred embodiment about 0.5-6% of the amine groups in the hydrocarbon amine polymer are reacted with the crosslinking agent. In another preferred embodiment about 2-12% of the amine groups in the hydrocarbon amine polymer are reacted with the crosslinking agent.

Crosslinking of the polymer can be achieved by reacting the polymer with a suitable crosslinking agent in an aqueous solution at about 25 ℃ for 18 hours to produce a colloid. The colloid is then combined with water or dried to a particulate solid. The particulate solid is then washed with water and dried under suitable conditions, such as at a temperature of about 50 ℃ for about 18 hours.

The hydrocarbon amine polymer may be alkylated to form the chelating agent of the invention. The term "alkylating agent" as used herein refers to a reagent which, when reacted with a hydrocarbon amine polymer, allows the nitrogen atom of the quaternary amine-containing moiety to be covalently linked to the main chain amine of one or more of the hydrocarbon amine polymers through an alkylene group of three or more carbon atoms. Suitable alkylating agents of the present invention may be quaternary ammonium compounds. Thus, another aspect of the invention relates toThere are quaternary amines of the formula,

wherein,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

In another aspect, X is a halide. Preferred values of n are 3-6. In another aspect, one or both of the alkyl groups is methyl.

Specific examples of quaternary ammonium compounds suitable as alkylating agents include:

(4-bromobutyl) dioctylmethylammonium bromide;

(3-bromopropyl) dodecyldimethylammonium bromide;

(3-chloropropyl) dodecyldimethylammonium bromide;

(3-bromopropyl) octyldimethylammonium bromide;

(3-chloropropyl) octyldimethylammonium bromide;

(3-iodobutyl) dioctylmethylammonium bromide;

(2, 3-epoxypropyl) decyl dimethyl ammonium bromide;

(3-chloropropyl) decyl dimethyl ammonium bromide;

(5-tosylpentyl) dodecyldimethylammonium bromide;

(6-bromohexyl) octyldimethylammonium bromide;

(12-bromododecyl) decyl dimethyl ammonium bromide;

(3-bromopropyl) tridecylammonium bromide;

(3-bromopropyl) behenyldimethylammonium bromide;

(6-bromohexyl) docosyldimethylammonium bromide;

(4-chlorobutyl) dodecyldimethylammonium bromide;

(3-chloropropyl) octadecyldimethylammonium bromide;

(3-chloropropyl) hexyldimethylammonium bromide;

(3-chloropropyl) methyldioctylammonium bromide;

(3-chloropropyl) methyldidecylammonium bromide;

(3-chloropropyl) cyclohexyldimethylammonium bromide;

(3-chloropropyl) tetradecyldimethylammonium bromide; and the like.

It will be appreciated that the above compounds may be used in halogenated form, including bromides, chlorides and iodides, as well as other negatively charged ions, such as acetates, nitrates, sulfates and p-toluenesulfonate.

Examples of one suitable method of preparing the alkylating agents, preferably quaternary ammonium compounds, of the present invention include tertiary amines having the formula,

wherein,

a step of reacting with an asymmetric dihalide having the formula,

X¹--(CH₂)_n--X²

wherein,

X¹is a chlorine-containing compound having a chlorine-containing group,

X²is bromine, and

n is an integer of 3 or more.

In another aspect, the tertiary amine may have two or all three alkyl or substituted alkyl groups having from 6 to about 24 carbon atoms. In the case of two alkyl groups, the remaining alkyl group has from 1 to about 5 carbon atoms. Typically, the alkylation reaction is carried out by combining the substituted tertiary amine with the appropriate dihalide in an organic solvent. An example of a suitable symmetric dihalide is dichloride. An example of a suitable dichloride is 1, 3-dichloropropane.

Preferred dihalides of the invention also include unsymmetrical dihalides. "asymmetric dihalide" is defined herein to mean dihalides in which the halogens are different and therefore have different reactivities as alkylating agents. Suitable examples of asymmetric dihalides include 1-bromo-3-chloropropane and 1-bromo-4-chlorobutane. In general, when the dihalide is a bromine/chlorine mixture, the terminally brominated molecule is more reactive than the terminally chlorinated molecule. Thus, an asymmetric dihalide reaction will result in a nearly exclusive reaction occurring at the bromine bearing end, while the chlorine bearing end is nearly unreactive. This relatively pure compound can then be used to alkylate the nitrogen on the hydrocarbon amine polymer by the reaction that occurs at the chlorine end. The use of an asymmetric dihalide avoids the undesirable side reactions that often occur with symmetric dihalides, both increasing the yield of alkylating agents containing quaternary amines and increasing the purity. Examples of suitable organic solvents include methanol, diethyl ether and the like. The preferred organic solvent is methanol.

The reaction is maintained at a temperature and for a time sufficient to allow the tertiary amine to react with the asymmetric dihalide. These parameters generally depend on the nature of the reactants and can be determined experimentally by one of ordinary skill in the art.

The reaction is terminated by removing the solvent by an appropriate method. The crude quaternary amine-containing alkylating agent is prepared for further reaction by methods known to those of ordinary skill in the art.

The hydrocarbon amine polymers are typically alkylated by combining the polymer with a quaternary amine-containing alkylating agent in an organic solvent or water. The amount of alkylating agent used in conjunction with the hydrocarbon amine polymer is generally sufficient to cause the alkylating agent to react with greater than about 5% of the reactive nitrogen atoms on the hydrocarbon amine polymer. Examples of suitable solvents include methanol, ethanol, acetonitrile, water, and the like. Preferred solvents are water and methanol.

It is particularly preferred in the present invention that the hydrocarbon amine polymer is a crosslinked poly (allylamine) wherein the substituent comprises (3-propyl) dodecyldimethylammonium chloride. Alternatively, the hydrocarbon amine polymer is a crosslinked poly (allylamine), wherein the substituent comprises butyl dioctylmethylammonium chloride. In addition, particularly preferred crosslinked poly (allylamine) s are crosslinked with epichlorohydrin which comprises about 0.5 to 6% of the amine in the polymer.

The hydrocarbon amine polymers of the present invention may then be treated with other materials to prepare compositions for oral administration of the hydrocarbon amine polymers.

The pharmaceutical compositions of the present invention are generally prepared by known methods using known and readily available ingredients. The hydrocarbon amine polymers may be used alone or in admixture with a carrier in the preparation of the compositions of the present invention, or diluted by a carrier, or packaged in a carrier in the form of a capsule, sachet, paper or other container. When the carrier is used as a diluent, it may be a solid, semi-solid or liquid material which acts as a carrier, excipient or medium for the polymer. Thus, the composition may be in the form of: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, syrups, sols, (solid or in a liquid medium), soft or hard gelatin capsules, sterile packaged powders, and the like. Examples of suitable carriers, excipients, and diluents include foods, beverages, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, and talc.

The negatively charged counterion of the pharmaceutical composition can comprise an organic ion, an inorganic ion, or a combination thereof. Inorganic ions suitable for use in the present invention include halides (especially chlorides), carbonates and bicarbonates. Suitable organic ions include acetate and benzoate salts.

The following examples further and specifically illustrate the invention. All parts and percentages are by weight unless otherwise indicated. Best mode for carrying out the invention

Example 1

Preparation of poly (allylamine) hydrochloride crosslinked with epichlorohydrin

In a 5 gallon container was added poly (allylamine) hydrochloride (1kg) from Nitto Boseki and water (4L). The mixture was stirred to dissolve the hydrochloride salt and the pH was adjusted by the addition of solid NaOH (284 g). The resulting solution was cooled to room temperature, and then the entire epichlorohydrin crosslinking agent (50mL) was added at once while stirring. The resulting mixture was gently stirred to a gum after about 35 minutes. The crosslinking reaction was continued at room temperature for 18 hours and then placed in portions into a blender with a total of 10L of water. Each batch was slowly stirred for about 3 minutes to form coarse particles and finally stirred for an additional 1 hour. The solid was collected by filtration, rinsed three times by suspending it in 10L, 15L and 20L of water, each time the suspension was stirred for 1 hour and then collected by filtration. The solid was rinsed once more suspended in isopropanol (17L), the mixture was stirred for 1 hour, and the solid was collected by filtration. The solid was dried in a vacuum oven at 50 ℃ for 18 hours to give about 677g of a particulate, brittle, white solid crosslinked polymer.

Example 2

Alkylation of crosslinked poly (allylamine) with (3-bromopropyl) dodecyldimethylammonium bromide

Crosslinked poly (allylamine) was prepared as described in example 1. The flask was charged with crosslinked poly (allylamine) (12.5 g; 6% crosslinked; ground to less than 30 mesh), (3-bromopropyl) dodecyldimethylammonium bromide (17.5 g; prepared by reaction of 1, 3-dibromopropane with N, N-dimethyl-1-aminododecane in diethylether) and methanol (334 mL). The mixture was heated to 65 ℃ while stirring, an aqueous sodium hydroxide solution (1.14g of a 50% solution) was added thereto when 65 ℃ was reached, and stirring was continued at 65 ℃ for 2 hours. Aqueous sodium hydroxide solution (1.14g of 50% solution) was added twice in succession, each time with continuous stirring at 65 ℃ for 2 hours. An additional aqueous sodium hydroxide solution (1.14g of 50% solution) was added and stirring was continued at 65 ℃ for 12 hours. The mixture was then cooled to room temperature.

The solid product was filtered off and washed with the suspension while stirring for 30 minutes, and filtered from the following liquid:

1.459 mL 2M NaCl (aqueous solution)

2.459 mL 2M NaCl (aq)

3.2L deionized water

4.2L deionized water

5.2L deionized water

6.2L deionized water

The resulting solid was then dried in a 60 ℃ blast furnace (forced-air oven) to yield 17.4g of an off-white solid. The solids were ground and screened through a 80 mesh screen.

EXAMPLE 3 alkylation of crosslinked poly (allylamine) with (3-bromopropyl) dodecyldimethylammonium bromide

Crosslinked poly (allylamine) was prepared as described in example 1. The flask was charged with crosslinked poly (allylamine) (12.5 g; 6% crosslinked; ground to less than 30 mesh), (3-bromopropyl) dodecyldimethylammonium bromide (35 g; prepared by reaction of 1, 3-dibromopropane with N, N-dimethyl-1-aminododecane in diethylether) and methanol (334 mL). The mixture was heated to 65 ℃ while stirring, an aqueous sodium hydroxide solution (1.99g of a 50% solution) was added thereto when 65 ℃ was reached, and stirring was continued at 65 ℃ for 2 hours. Aqueous sodium hydroxide solution (1.99g of 50% solution) was added twice in succession, each time with continuous stirring at 65 ℃ for 2 hours. An additional aqueous sodium hydroxide solution (1.99g of 50% solution) was added and stirring was continued at 65 ℃ for 12 hours. The mixture was then cooled to room temperature.

1.459 mL 2M NaCl (aqueous solution)

2.459 mL 2M NaCl (aq)

3.2L deionized water

4.2L deionized water

5.2L deionized water

6.2L deionized water

The resulting solid was then dried in a 60 ℃ blast furnace to give 25.6g of an off-white solid. The solids were ground and screened through a 80 mesh screen.

Example 4

Crosslinked poly (allylamine) was prepared as described in example 1, but instead of 50mL epichlorohydrin was used, 16.7mL was used. A flask was charged with crosslinked poly (allylamine) (12.5 g; 2% crosslinked; ground to less than 30 mesh), (3-bromopropyl) dodecyldimethylammonium bromide (140.8 g; prepared by reaction of 1, 3-dibromopropane with N, N-dimethyl-1-aminododecane in diethylether) and methanol (334 mL). The mixture was heated to 65 ℃ while stirring, an aqueous sodium hydroxide solution (7.1g of a 50% solution) was added thereto when 65 ℃ was reached, and stirring was continued at 65 ℃ for 2 hours. Aqueous sodium hydroxide solution (7.1g of 50% solution) was added twice in succession, each time with continuous stirring at 65 ℃ for 2 hours. An additional aqueous sodium hydroxide solution (1.99g of 50% solution) was added and stirring was continued at 65 ℃ for 12 hours. The mixture was then cooled to room temperature.

1.1.7L 2M NaCl (aqueous solution)

2.1.7L 2M NaCl (aqueous solution)

3.8L deionized water

4.8L deionized water

5.8L deionized water

6.8L deionized water

7.4L deionized water

The resulting solid was then dried in a 60 ℃ blast furnace to give 39.8g of an off-white solid. The solids were ground and screened through a 80 mesh screen.

Example 5

Crosslinked poly (allylamine) was prepared as described in example 1. The flask was charged with crosslinked poly (allylamine) (12.5 g; 6% crosslinked; ground to less than 30 mesh), (3-bromopropyl) dodecyldimethylammonium bromide (30.2 g; prepared by reaction of 1, 3-dibromopropane with N, N-dimethyl-1-aminododecane in diethylether) and methanol (334 mL). The mixture was heated to 65 ℃ while stirring, an aqueous sodium hydroxide solution (2.0g of a 50% solution) was added thereto when 65 ℃ was reached, and stirring was continued at 65 ℃ for 2 hours. Aqueous sodium hydroxide solution (2.0g of 50% solution) was added twice in succession, each time with continuous stirring at 65 ℃ for 2 hours. An additional aqueous sodium hydroxide solution (2.0g of 50% solution) was added and stirring was continued at 65 ℃ for 12 hours. The mixture was then cooled to room temperature.

1.800 mL 2M NaCl (aqueous solution)

2.800 mL 2M NaCl (aqueous solution)

3.2L deionized water

4.2L deionized water

5.1L deionized water

The resulting solid was then dried in a 60 ℃ blast furnace to give 16.8g of an off-white solid. The solids were ground and screened through a 80 mesh screen.

Example 6

Alkylation of crosslinked poly (allylamine) with (6-bromohexyl) octyldimethylammonium bromide

Crosslinked poly (allylamine) was prepared as described in example 1. The flask was charged with crosslinked poly (allylamine) (12.5 g; 6% crosslinked; ground to less than 30 mesh), (6-bromohexyl) octyldimethylammonium bromide (33.7 g; prepared by reaction of 1, 6-dibromohexane with N, N-dimethyl-1-aminooctane in diethyl ether) and methanol (334 mL). The mixture was heated to 65 ℃ while stirring, an aqueous sodium hydroxide solution (1.68g of a 50% solution) was added thereto when 65 ℃ was reached, and stirring was continued at 65 ℃ for 2 hours. Aqueous sodium hydroxide solution (1.68g of 50% solution) was added twice in succession, each time with continuous stirring at 65 ℃ for 2 hours. An additional aqueous sodium hydroxide solution (1.68g of 50% solution) was added and stirring was continued at 65 ℃ for 12 hours. The mixture was then cooled to room temperature.

1.1L 2M NaCl (aqueous solution)

2.1L 2M NaCl (aqueous solution)

3. Repeating 1L of deionized water until the conductivity of the solution is less than 1mS/cm

The resulting solid was then dried in a 60 ℃ blast furnace to give.15.7 g of an off-white solid. The solids were ground and screened through a 80 mesh screen.

Example 7

Alkylation of crosslinked poly (allylamine) with (4-butyl) dioctylmethylammonium bromide

Crosslinked poly (allylamine) was prepared as described in example 1, but using 25mL instead of 50mL of epichlorohydrin crosslinker. A flask was charged with crosslinked poly (allylamine) (12.5 g; 3% crosslinked; ground to less than 30 mesh), (4-bromobutyl) dioctylmethylammonium bromide (65.8g crude; prepared by reaction of 1, 4-dibromobutane with N, N-dioctylmethylamine in methanol) and methanol (334 mL). The mixture was heated to 65 ℃ while stirring, an aqueous sodium hydroxide solution (3.28g of a 50% solution) was added thereto when 65 ℃ was reached, and stirring was continued at 65 ℃ for 2 hours. Aqueous sodium hydroxide solution (3.28g of 50% solution) was added twice in succession, each time with continuous stirring at 65 ℃ for 2 hours. An additional aqueous sodium hydroxide solution (3.28g of 50% solution) was added and stirring was continued at 65 ℃ for 12 hours. The mixture was then cooled to room temperature.

1.800 mL of methanol

2.1000 mL of methanol

3.890 mL 2M NaCl (aq)

4.890 mL 2M NaCl (aq)

5.2L deionized water

6.2L deionized water

The resulting solid was then dried in a 60 ℃ blast furnace to give 27.1g of an off-white solid. The solids were ground and screened through a 80 mesh screen.

Example 8

Preparation of (3-chloropropyl) dodecyl diethyl ammonium bromide

Into a 2L three necked round bottom flask equipped with an air condenser and magnetic stirrer was charged N, N-dimethyldodecylamine (297.24g, 1.40mol), 1-bromo-3-chloropropane (220.44g, 1.40mol) and methanol (250 mL). The reaction was maintained at 65 ℃ for 24 hours. Methanol was removed by rotary evaporation under reduced pressure to give a brown precipitate. Methyl-t-butyl ether (2L) was added to the sediment to yield a white solid. The mixture was stirred for 2 hours and the resulting semi-crystalline white particles were collected by vacuum filtration. These particles were dried in a vacuum oven at 35 ℃ for 24 hours to give 228.2g (0.61mol, 44%) of the title compound.

Example 9

Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) dodecyldimethylammonium bromide

Crosslinked poly (allylamine) was prepared as described in example 1, except that the final crosslinking was 3 mole%. In a 2L three-necked flask equipped with a thermometer and condenser were placed crosslinked poly (allylamine) (25 g; 3% crosslinked; ground to 10 mesh), (3-chloropropyl) dodecyldimethylammonium bromide (280g, 0.755 mol; prepared as described in example 8) and water (750 mL). The mixture was heated to 100 ℃ while stirring, and after reaching 100 ℃ 10 aqueous sodium hydroxide solution (6.1g of 50% solution) was added at regular intervals over 8 hours. Stirring was continued at 100 ℃ for 16 hours. The mixture was then cooled to room temperature.

Concentrated hydrochloric acid (50mL) was added and the mixture was stirred for 10 minutes, then filtered to collect the solid. The solid was rinsed on the funnel with 1.5L of methanol. The solid product was filtered off and washed with the suspension while stirring for 30 minutes, and filtered from the following liquid:

1.1L of methanol

2.3.3L 2M NaCl (aqueous solution)

3.3.3L 2M NaCl (aqueous solution)

4.3.3L 2M NaCl (aqueous solution)

5.8L deionized water

The solid was resuspended in deionized water (4L) and the pH adjusted to 2.2 with HCl. The solid (178.6g) was collected by filtration and then dried in a blast furnace at 60 ℃ to give 111g of a solid. The solids were ground and screened through a 80 mesh screen.

Example 10

Alkylation of crosslinked poly (allylamine) with (3-chloro) propyl-dimethylhexylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (3-chloro) propyl-dimethylhexylammonium bromide (216.4g), to give 85.6g of product.

Example 11

Alkylation of crosslinked poly (allylamine) with (3-propyl) dimethylcyclohexylammonium bromide

Example 9 was repeated, using (3-chloropropyl) dimethylcyclohexylammonium bromide (213.2g) in place of (3-chloropropyl) dodecyldimethylammonium bromide to give 86.4g of product.

Example 12

Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) dimethyloctylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (3-chloropropyl) dimethyloctylammonium bromide (237.7g), to give 104.6g of product.

Example 13

Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) dimethyldecylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (3-chloropropyl) dimethyldecylammonium bromide (269.4g), to give 101.7g of product.

Example 14

Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) dimethyltetradecylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (3-chloropropyl) dimethyltetradecylammonium bromide (301.2g) to give 112.3g of product.

Example 15

Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) methyldioctylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (3-chloropropyl) methyldioctylammonium bromide (272g) and adding 5.5g of aqueous NaOH solution each time, to give 96.8g of product.

Example 16

Alkylation of crosslinked poly (allylamine) with (4-chlorobutyl) methyldioctylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (4-chlorobutyl) methyldioctylammonium bromide (241.6g) and adding 4.4g of aqueous NaOH each time, to give 80.0g of product.

Example 17

Alkylation of crosslinked poly (allylamine) with (4-chlorobutyl) dimethyldodecylammonium bromide

Example 9 was repeated, using (4-chlorobutyl) dimethyldodecylammonium bromide (290.5g) in place of (3-chloropropyl) dodecyldimethylammonium bromide to give 93.9g of product.

Example 18

Alkylation of crosslinked poly (allylamine) with (5-chloropentyl) methyldodecylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (5-chloropentyl) methyldodecylammonium bromide (150.6g) and adding 3.0g of aqueous NaOH solution each time to give 46.2g of product.

Example 19

Alkylation of crosslinked poly (allylamine) with (10-bromodecyl) trimethylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (10-bromodecyl) trimethylammonium bromide (271.0 g). Water (100mL) was added after 4 hours and water (100mL) was added after 8 hours to give 101.8g of product.

EXAMPLE 20 alkylation of crosslinked poly (allylamine) with (6-chlorohexyl) dimethyldecylammonium bromide

Example 9 was repeated, replacing (3-chloropropyl) dodecyldimethylammonium bromide with (6-chlorohexyl) dimethyldecylammonium bromide (145.2g) and adding 3.0g of aqueous NaOH each time, to give 46.2g of product.

Example 21

Preparation of (4-chlorobutyl) dimethyldodecylammonium bromide

Into a 1000mL round bottom flask equipped with an air condenser and magnetic stirrer were added N, N-dimethyldodecylamine (308.8g, 1.45mol), 1-bromo-4-chlorobutane (249.98g, 1.45mol) and 300mL of methanol. The reaction was held at 65 ℃ for 48 hours. The solvent was removed by rotary evaporation under reduced pressure to give a brown oil. To this oil was added 100mL of butanol. The mixture was distilled under vacuum at 30-50 ℃ until the distillate ceased to collect, yielding 384.47g (0.99mol, 69%) of the title compound.

Example 22

Preparation of (2-chloroethyl) dimethyldodecylammonium bromide

A1000 mL round bottom flask equipped with an air condenser and magnetic stirrer was charged with N, N-dimethyldodecylamine (186.46g, 0.875mol), 1-bromo-2-chloroethane (125.60g, 0.875mol) and methanol (150 mL). The reaction was held at 65 ℃ for 48 hours. The solvent was removed by rotary evaporation under reduced pressure to give a brown oil. The oil was stirred in a beaker with t-butyl methyl ether (2L) to form a brownish white precipitate. The solid was collected by vacuum filtration. The solid was dried in a vacuum oven at 30 ℃ overnight to give 197.0g (0.55mol, 63%) of the title compound.

Example 23

Comparison of reactivity towards Quaternary ammonium alkylating Agents

Alkylating agents (4-chlorobutyl) dodecyldimethylammonium bromide, (3-chloropropyl) dodecyldimethylammonium bromide and (2-chloroethyl) dodecyldimethylammonium bromide were prepared as described in examples 21, 8 and 22, respectively. Each alkylating agent was separately reacted with the poly (allylamine) prepared in example 9 under the same conditions. The reactivity of each alkylating agent with the amine of the poly (allylamine) backbone was evaluated and compared to give the following results:

alkylating agents	Starting polymers	Alkylated polymers	Alkylation (%)
alkylating agents	Starting polymers	Alkylated polymers	Alkylation (%)	(4-chlorobutyl) dodeca dimethyl ammonium bromide n ═ 4	25g	94g	109
(3-chloropropyl) dodecyl dimethyl ammonium bromide n ═ 3	25g	111g	124	(4-chlorobutyl) dodeca dimethyl ammonium bromide n ═ 4	25g	94g	109
(3-chloropropyl) dodecyl dimethyl ammonium bromide n ═ 3	25g	111g	124	(2-chloroethyl) dodecyl dimethyl ammonium bromide n ═ 2	25g	28g	15

Elemental analysis was used to obtain the percent alkylation. One-fold alkylation for each amine corresponds to 100% alkylation; twice as much alkylation for each amine corresponds to 200% alkylation; three-fold alkylation for each amine corresponds to 300% alkylation. The N/C ratio of the polymer was obtained from elemental analysis. Since the alkylating agent has a different N/C ratio than the base polymer, it can be directly determined how much of a given alkylating agent must be bound to the polymer to improve the N/C ratio of the starting materials and the final product. This result is expressed as the percentage of the total amines of the polymer that have been alkylated, a number greater than 100% indicating that a single amine is multiply alkylated. For example, the N/C ratio of the starting material is 0.313, and after alkylation with an alkylating agent having N-3, the N/C ratio becomes 0.0922, indicating 124% alkylation. The calculation formula is as follows:

percent alkylation ═ 3.2^*(N/C)-1)/(1-N/C^*17) Where 3.2 is the C/N ratio of the starting material and 17 is the C/N ratio of the alkylating agent (for alkylating agents where N is 2 and 4, the values are 16 and 18, respectively).

From these results, it is clear that the alkylating agent of n-2 is much less effective in alkylating the amine of an amine polymer than the alkylating agents of n-3 and n-4. We hypothesize that this effect is due to the influence of the quaternary amine on the reactivity of the alkyl halide. It can therefore be concluded that the use of alkylating agents in which the quaternary amine is greater than 2 carbon atoms removed from the carbon atoms of the halogen-bearing alkyl halide leads to unexpected improvements in alkylating agents having less than 2 carbon atoms.

Example 24

Preparation of (3-chloropropyl) cyclohexyl dimethyl ammonium bromide

Into a 1L three-necked Morton flask equipped with an air condenser and a magnetic stirrer were charged N, N-dimethylcyclohexylamine (210.46g, 1.65mol), 1-bromo-3-chloropropane (259.99g, 1.65mol) and methanol (250 mL). The reaction was maintained at 65 ℃ for 24 hours. Methanol was removed by rotary evaporation under reduced pressure to give a brown precipitate. To the sediment was added tert-butyl methyl ether (600mL) to form an oil. The liquid was decanted from the oil and a second batch of methyl tertiary butyl ether (600mL) was added. The mixture was stirred and the liquid decanted from the thick sediment. Diethyl ether (600mL) was added to the sediment to form a white semi-solid layer. The mixture was stirred and the liquid was removed. The white solid was placed in a vacuum oven at 35 ℃ for 24 hours to give 404.9g (1.42mol, 85%) of the title compound.

Example 25

Preparation of (3-chloropropyl) tetradecyldimethylammonium bromide

N, N-dimethyltetradecylamine (311.59g, 1.29mol), 1-bromo-3-chloropropane (203.09g, 1.29mol) and methanol (250mL) were charged in a 1L three-necked round-bottomed flask equipped with an air condenser and a magnetic stirrer. The reaction was maintained at 65 ℃ for 24 hours. Methanol was removed by rotary evaporation under reduced pressure to give a precipitate. To the residue was added methyl tert-butyl ether (500mL) to slowly form a white solid. The mixture was stirred for 1.5 hours and a white paste-like mass was collected by vacuum filtration. The solid was placed in a vacuum oven at 35 ℃ for 24 hours to yield 420g (1.05mol, 82%) of the title compound.

Example 26

Preparation of (3-chloropropyl) hexyldimethylammonium bromide

A500 mL three necked round bottom flask equipped with an air condenser and magnetic stirrer was charged with N, N-dimethylhexylamine (199.46g, 1.54mol), 1-bromo-3-chloropropane (243.00g, 1.54mol) and methanol (250 mL). The reaction was maintained at 65 ℃ for 24 hours. The solvent was removed by rotary evaporation under reduced pressure to give 445.8g (1.55mol, 100%) of a brown viscous oil.

Example 27

Preparation of (3-chloropropyl) octyl dimethyl ammonium bromide

A500 mL three-necked round bottom flask equipped with an air condenser and magnetic stirrer was charged with N, N-dimethyloctylamine (110.02g, 0.70mol), 1-bromo-3-chloropropane (110.2g, 0.70mol) and methanol (150 mL). The reaction was maintained at 65 ℃ for 24 hours. The solvent was removed by rotary evaporation under reduced pressure to give a brown oil. The oil was extracted by mixing with methyl-tert-butyl ether (600mL) in a large crusher and the excess solvent was decanted. This was repeated 3 times. Finally, the oil was extracted with diethyl ether (600mL) and excess solvent was decanted off. The viscous oil was dried overnight in a vacuum oven at 35 deg.C to yield 174.14g (0.55mol, 79%) of the title compound.

Example 28

Preparation of (3-chloropropyl) octadecyl dimethyl ammonium bromide

A1000 mL round bottom flask equipped with an air condenser and magnetic stirrer was charged with N, N-dimethyloctadecylamine (301.0g, 1.01mol), 1-bromo-3-chloropropane (170.0g, 1.08mol) and methanol (200 mL). The reaction was held at 65 ℃ for 18 hours. The solvent was removed by rotary evaporation under reduced pressure to give a clear oil. After the oil was poured into a beaker filled with methyl ethyl ketone (250mL), a white precipitate formed. The solid was collected by vacuum filtration and then resuspended in methyl ethyl ketone (250 mL). This was repeated twice and finally the solid was collected in vacuo. The solid was placed in a vacuum oven at 30 ℃ overnight to yield 274.9g (0.59mol, 58%) of the title compound.

Example 29

Preparation of (3-chloropropyl) decyl dimethyl ammonium bromide

A1000 mL round bottom flask equipped with an air condenser and magnetic stirrer was charged with N, N-dimethyldecylamine (200.0g, 1.08mol), 1-bromo-3-chloropropane (170g, 1.08mol) and methanol (200 mL). The reaction was held at 65 ℃ for 18 hours. The solvent was removed by rotary evaporation under reduced pressure and distilled under high vacuum to give a brown oil. The oil was placed in a beaker and stirred with a 1: 1 solution of hexane/tert-butyl methyl ether (400mL) to form a white precipitate. The solid was collected by vacuum filtration and dried in a vacuum oven at 30 ℃ overnight to yield 305.0g (0.089mol, 82%) of the title compound.

Example 30

Preparation of (3-chloropropyl) dioctylmethylammonium bromide

Into a 1L three necked round bottom flask equipped with an air condenser and magnetic stirrer was charged N, N-dioctylmethylamine (202.48g, 0.79mol), 1-bromo-3-chloropropane (124.8g, 0.79mol) and methanol (250 mL). The reaction was maintained at 65 ℃ for 2 days. Methanol was removed by rotary evaporation under reduced pressure to give an oil. To the oil were added methyl ethyl ketone (50mL) and hexane (200mL) to slowly form a white solid. The solvent was decanted from the mixture. The remaining solid was washed twice with hexane (50 mL). The solid was placed in a vacuum oven at 35 ℃ for 24 hours to give 259g (0.625mol, 79%) of a waxy solid.

Example 31

Preparation of (3-chloropropyl) didecylmethylammonium bromide

Into a 2L three necked round bottom flask equipped with an air condenser and magnetic stirrer was charged N, N-didecylmethylamine (65.49g, 0.21mol), 1-bromo-3-chloropropane (33.06g, 0.21mol) and methanol (250 mL). The reaction was maintained at 65 ℃ for 6 days. Methanol was removed by rotary evaporation under reduced pressure to give an oil. Hexane (200mL) was added to the oil and a white solid was slowly formed. The solvent was decanted from the mixture. The remaining solid was dried under vacuum overnight to yield 81.67g (0.17mol, 82%) of the title compound.

Example 32

Preparation of (6-chlorohexyl) dodecadimethyl ammonium bromide

Into a 500mL round bottom flask equipped with an air condenser and magnetic stirrer was charged N, N-dioctylmethylamine (95.13g, 0.513mol), 1-bromo-3-chloropropane (102.40g, 0.513mol) and tert-butyl methyl ether (200 mL). The reaction was held at 58 ℃ for 14 hours during which time a white precipitate formed. The reaction was cooled to room temperature and tert-butyl methyl ether (350mL) was added. The solid was collected by vacuum filtration. The mother liquor was allowed to continue the reaction at 60 ℃ and the solid was collected in a similar manner. The solids obtained in both times were combined and dried in a vacuum oven at 35 ℃ for 24 hours to give 127.36g of the title compound.

Example 33

Preparation of (4-chlorobutyl) dioctylmethylammonium bromide

A500 mL round bottom flask equipped with an air condenser and magnetic stirrer was charged with N-methyldioctylamine (201.83g, 0.790mol), 1-bromo-4-chlorobutane (135.517g, 0.790mol) and methanol (250 mL). The reaction was held at 68 ℃ for 48 hours. The reaction was cooled to room temperature and the solvent was removed by rotary evaporation until a viscous oil was obtained. Removal of the solvent at 50 ℃ under high vacuum was continued to give 333.53g of a thick brown oil.

Example 34

Preparation of (5-chloropentyl) dodecamethylammonium bromide

A500 mL round bottom flask equipped with an air condenser and magnetic stirrer was charged with N, N-dimethyldodecylamine (230.17g, 1.078mol), 1-bromo-5-chloropentane (199.77g, 1.076mol) and tert-butyl methyl ether (250 mL). The reaction became a white viscous with a precipitate after heating at 60 ℃ for 2 hours. Additional tert-butyl methyl ether (250mL) was added. The reaction was held at 60 ℃ for 24 hours. The reaction was cooled to room temperature and the solid collected by vacuum filtration. The solid was dried in a vacuum oven at 35 ℃ for 24 hours to give 207.40g of the title compound.

Example 35

Preparation of crosslinked poly (vinylamine); with (3-chloropropyl) dimethyl

Dodecylammonium bromide alkylated cross-linked poly (vinylamine)

Poly (vinylamine) free base (mw 40,000; product of Air Products; 62.5g) was dissolved in water (188mL) and methanol (250 mL). Epichlorohydrin (2.8g) was added and the mixture was stirred until a gum was formed. The gum was dissolved and suspended in water (13L). The solid was collected by filtration and dried in a 60 ℃ blast furnace to give 75.2g of a solid. The solid was ground and sieved through a 10 mesh sieve.

The ground solid (14.8g) was reacted in a similar manner to example 9 using 140g of (3-chloropropyl) dimethyldodecylammonium bromide and 30g of aqueous base to give 57.7g of product. Comparison of efficiencies for examples 10, 12, 13 and 19

Examples 10, 12, 13 and 19 were made with alkylating agents of the form:

wherein,

examples	n	m	Longest hydrophobic alkyl group	All carbon atoms
examples	n	m	Longest hydrophobic alkyl group	All carbon atoms	10121319	33310	68100	681010	11131513

Examples 10, 12 and 13 are examples of the present invention containing a terminal hydrophobic alkyl group. The chain length of the hydrophobic alkyl group is 6 in example 10 and 8 and 10 in examples 12 and 13, respectively. But the hydrocarbon chain with one end attached to the quaternary amine and the other end attached to the amine on the polymer backbone (n-10) in example 19 was not considered as the terminal hydrophobic group.

These examples are considered to be a proper comparison of the difference in efficiency of the non-or terminal hydrophobic groups of the alkylating agent with those inside the alkylating agent, and the difference between the quaternary amine and the amine polymer. Comparative example 19 (example of hydrophobe between quaternary amine and amine polymer) these examples were selected to have the same total number of carbon atoms (example 12), or the same individual hydrophobe length (example 13), or the same number of carbon atoms in the unbranched segments (11; example 10). In addition, the amount of alkylating agent attached to the polymer backbone in these polymers is similar based on the yield of the alkylation reaction.

In vivo tests of the chelators prepared in examples 10, 12, 13 and 19 were performed on rats. Animals were injected subcutaneously with bile acids (cholic acid and chenocholic acid) labeled with 14C solution. The labeled bile acid is present in the same ratio as in gall bladder bile (3: 1; cholic acid: chenocholic acid). They enter the gallbladder and interact with the animal's own bile. The animals were then fed the drug-containing feed for 36 hours and feces were collected over the last 29 hours. Fecal samples were processed and radioactivity was counted. The results are expressed as the percentage or ratio of radiolabeled excreta to those of animals not fed the chelator.

EXAMPLES Activity^*

10 184％

12 200％

13 184％

19 143％

Percentage of radioactivity excreted per gram of feces relative to control without chelator.

These data demonstrate that for chelants with equivalent "hydrophobe" chain lengths, chelants with hydrophobic alkyl groups at the end have a significant advantage over chelants with hydrophobic alkyl groups on the inside. Equivalents of the same

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims

1. A crosslinked poly (allylamine) polymer comprising an amine substituent attached to said polymer, said substituent comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group having 3 or more carbon atoms, and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having 6 to about 24 carbon atoms and the remaining terminal substituents are each an alkyl group having 1 to about 5 carbon atoms.

2. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 3 carbon atoms, the hydrophobic alkyl group is octyl, and the remaining terminal substituents are methyl.

3. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 3 carbon atoms, the hydrophobic alkyl group is a decyl group, and the remaining terminal substituents are methyl groups.

4. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 3 carbon atoms, hydrophobic alkyl is dodecyl, and the remaining terminal substituents are methyl.

5. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 4 carbon atoms, the hydrophobic alkyl group is octyl, and the remaining terminal substituents are methyl.

6. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 4 carbon atoms, the hydrophobic alkyl group is a decyl group, and the remaining terminal substituents are methyl groups.

7. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 4 carbon atoms, the hydrophobic alkyl group is a dodecyl group, and the remaining terminal substituents are methyl groups.

8. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 5 carbon atoms, the hydrophobic alkyl group is octyl, and the remaining terminal substituents are methyl.

9. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 5 carbon atoms, the hydrophobic alkyl group is a decyl group, and the remaining terminal substituents are methyl groups.

10. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 5 carbon atoms, the hydrophobic alkyl group is a dodecyl group, and the remaining terminal substituents are methyl groups.

11. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 6 carbon atoms, the hydrophobic alkyl group is octyl, and the remaining terminal substituents are methyl.

12. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 6 carbon atoms, the hydrophobic alkyl group is a decyl group, and the remaining terminal substituents are methyl groups.

13. The crosslinked poly (allylamine) polymer of claim 1, wherein the alkylene has 6 carbon atoms, the hydrophobic alkyl group is a dodecyl group, and the remaining terminal substituents are methyl groups.

14. The crosslinked poly (allylamine) polymers are prepared by a process comprising reacting a crosslinked poly (allylamine) with a quaternary amine-containing compound having the formula,

wherein,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

15. The crosslinked poly (allylamine) polymer of claim 14, wherein n is from 3 to about 6.

16. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 3, at least one alkyl group is an octyl group, and the remaining alkyl groups are methyl groups.

17. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 3, at least one alkyl group is a decyl group, and the remaining alkyl groups are methyl groups.

18. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 3, at least one alkyl group is dodecyl, and the remaining alkyl groups are methyl.

19. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 4, at least one alkyl group is an octyl group, and the remaining alkyl groups are methyl groups.

20. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 4, at least one alkyl group is a decyl group, and the remaining alkyl groups are methyl groups.

21. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 4, at least one alkyl group is dodecyl, and the remaining alkyl groups are methyl.

22. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 5, at least one alkyl group is an octyl group, and the remaining alkyl groups are methyl groups.

23. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 5, at least one alkyl group is a decyl group, and the remaining alkyl groups are methyl groups.

24. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 5, at least one alkyl group is dodecyl, and the remaining alkyl groups are methyl.

25. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 6, at least one alkyl group is an octyl group, and the remaining alkyl groups are methyl groups.

26. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 6, at least one alkyl group is a decyl group, and the remaining alkyl groups are methyl groups.

27. The crosslinked poly (allylamine) polymer of claim 15, wherein n is 6, at least one alkyl group is dodecyl, and the remaining alkyl groups are methyl.

28. A hydrocarbyl amine polymer comprising an amine substituent attached to said polymer, the substituent comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group having 3 or more carbon atoms, and wherein at least two of the three terminal substituents of the quaternary amine are hydrophobic alkyl groups having 6 to about 24 carbon atoms and the other terminal substituent is an alkyl group having 1 to about 5 carbon atoms.

29. The hydrocarbon amine polymer of claim 28, wherein the polymer is crosslinked.

30. A hydrocarbon amine polymer comprising an amine substituent attached to said polymer, said substituent comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group of 3 or more carbon atoms, and wherein the three terminal substituents of the quaternary amine are hydrophobic alkyl groups of 6 to about 24 carbon atoms.

31. The hydrocarbon amine polymer of claim 30 where the polymer is crosslinked.

32. A crosslinked hydrocarbon amine polymer prepared by a process comprising reacting a crosslinked hydrocarbon amine polymer with a quaternary amine-containing compound having the formula,

wherein,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

33. The crosslinked hydrocarbon amine polymer of claim 32, wherein the polymer is a poly (vinylamine) polymer.

34. The crosslinked hydrocarbon amine polymer of claim 32, wherein the polymer is a poly (allylamine) polymer.

35. The crosslinked hydrocarbon amine polymer of claim 32, wherein the polymer is a poly (aziridine) polymer.

36. A method of binding bile salts in a mammal comprising orally administering to the mammal a therapeutic amount of a cross-linked poly (allylamine) polymer having an amine substituent group attached to said polymer, the substituent group comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group having 3 or more carbon atoms, and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having from 6 to about 24 carbon atoms and the remaining terminal substituents are each independently an alkyl group having from 1 to about 5 carbon atoms.

37. A method of binding bile salts of a mammal comprising orally administering to the mammal a therapeutic amount of a hydrocarbon amine polymer comprising an amine substituent group attached to said polymer, said substituent group comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group having 3 or more carbon atoms and wherein at least two of the three terminal substituents of the quaternary amine are hydrophobic alkyl groups having from 6 to about 24 carbon atoms and the other terminal substituent is an alkyl group having from 1 to about 5 carbon atoms.

38. A method of lowering blood cholesterol in a mammal comprising orally administering to the mammal a therapeutic amount of a cross-linked poly (allylamine) polymer having an amine substituent attached to said polymer, the substituent comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group of 3 or more carbon atoms and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group of 6 to about 24 carbon atoms and the remaining terminal substituents are each independently an alkyl group of 1 to about 5 carbon atoms.

39. A method of treating atherosclerosis in a mammal comprising orally administering to the mammal a therapeutic amount of a cross-linked poly (allylamine) polymer having an amine substituent group attached to said polymer, said substituent group comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group having 3 or more carbon atoms, and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having 6 to about 24 carbon atoms and the remaining terminal substituents are each independently an alkyl group having 1 to about 5 carbon atoms.

40. A method of treating hypercholesterolemia in a mammal comprising orally administering to the mammal a therapeutic amount of a cross-linked poly (allylamine) polymer having an amine substituent attached to said polymer, the substituent comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group of 3 or more carbon atoms and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group of 6 to about 24 carbon atoms and the remaining terminal substituents are each independently an alkyl group of 1 to about 5 carbon atoms.

41. A method of lowering blood lipid levels in a mammal comprising orally administering to the mammal a therapeutic amount of a cross-linked poly (allylamine) polymer having an amine substituent group attached to said polymer, said substituent group comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group having 3 or more carbon atoms, and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having from 6 to about 24 carbon atoms and the remaining terminal substituents are each independently an alkyl group having from 1 to about 5 carbon atoms.

42. A quaternary ammonium compound comprising

Wherein,

r represents alkyl, at least one of which has 6 to about 24 carbon atoms and the others each having 1 to 5 carbon atoms,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

43. The compound of claim 42, wherein one or both of said alkyl groups is methyl.

44. The compound of claim 43, wherein n is from 3 to about 8.

45. The compound of claim 44, wherein X is halide.

46. A quaternary ammonium compound comprising

Wherein,

r represents an alkyl group, at least two of which have from 6 to about 24 carbon atoms and the remaining one of which has from 1 to 5 carbon atoms,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

47. The compound of claim 46, wherein one alkyl is methyl.

48. The compound of claim 47, wherein n is from 3 to about 8.

49. The compound of claim 48, wherein X is halide.

50. A quaternary ammonium compound comprising

Wherein,

r represents alkyl groups each having from 6 to about 24 carbon atoms,

n is an integer of 3 or more,

x is a leaving group, and

y is a negatively charged counterion.

51. The compound of claim 50, wherein n is from 3 to about 8.

52. The compound of claim 51, wherein X is halide.

53. A process for preparing a quaternary ammonium compound of the structure,

comprising reacting a tertiary amine of the formula

Wherein,

r represents an alkyl group, at least one of which has 6 to about 24 carbon atoms, the remainder

Each having from 1 to 5 carbon atoms,

reacting with an asymmetric dihalide of the formula,

X¹--(CH₂)_n--X²

wherein,

X¹is a chlorine-containing compound having a chlorine-containing group,

X²is bromine, and

n is an integer of 3 or more.

54. A process for preparing a quaternary ammonium compound of the structure,

comprising reacting a tertiary amine of the formula

Wherein,

r represents an alkyl group, at least two of which have from 6 to about 24 carbon atoms, the remainder

One having from 1 to 5 carbon atoms and one having from 1 to 5 carbon atoms,

reacting with an asymmetric dihalide of the formula,

X¹--(CH₂)_n--X²

wherein

X¹Is a chlorine-containing compound having a chlorine-containing group,

X²is bromine, and

n is an integer of 3 or more.

55. A process for preparing a quaternary ammonium compound of the structure,

comprising reacting a tertiary amine of the formulaWherein,

r represents an alkyl group, all three of which each have from 6 to about 24 carbon atoms, with an asymmetric dihalide of the formula,

X¹--(CH₂)_n--X²wherein,

X¹is a chlorine-containing compound having a chlorine-containing group,

X²is bromine, and

n is an integer of 3 or more.

56. A poly (allylamine) polymer comprising an amine substituent attached to said polymer, the substituent comprising a quaternary amine-containing moiety wherein the nitrogen atom of said quaternary amine moiety is attached to the amine of the polymer through an alkylene group of 3 or more carbon atoms, and wherein at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group of 6 to about 24 carbon atoms, and the remaining terminal substituents are each independently an alkyl group of 1 to about 5 carbon atoms.

57. The poly (allylamine) polymer of claim 56, wherein the alkylene has 3 carbon atoms, the hydrophobic alkyl group is octyl, and the remaining terminal substituents are methyl.

58. The poly (allylamine) polymer of claim 56, wherein the alkylene has 3 carbon atoms, hydrophobic alkyl is decyl, and the remaining terminal substituents are methyl.

59. The poly (allylamine) polymer of claim 56, wherein the alkylene has 3 carbon atoms, hydrophobic alkyl is dodecyl, and the remaining terminal substituents are methyl.

60. The poly (allylamine) polymer of claim 56, wherein the alkylene has 4 carbon atoms, the hydrophobic alkyl group is octyl, and the remaining terminal substituents are methyl.

61. The poly (allylamine) polymer of claim 56, wherein the alkylene has 4 carbon atoms, hydrophobic alkyl is decyl, and the remaining terminal substituents are methyl.

62. The poly (allylamine) polymer of claim 56, wherein the alkylene has 4 carbon atoms, hydrophobic alkyl is dodecyl, and the remaining terminal substituents are methyl.

63. The poly (allylamine) polymer of claim 56, wherein the alkylene has 5 carbon atoms, the hydrophobic alkyl group is octyl, and the remaining terminal substituents are methyl.

64. The poly (allylamine) polymer of claim 56, wherein the alkylene has 5 carbon atoms, hydrophobic alkyl is decyl, and the remaining terminal substituents are methyl.

65. The poly (allylamine) polymer of claim 56, wherein the alkylene has 5 carbon atoms, hydrophobic alkyl is dodecyl, and the remaining terminal substituents are methyl.

66. The poly (allylamine) polymer of claim 56, wherein the alkylene has 6 carbon atoms, the hydrophobic alkyl is octyl, and the remaining terminal substituents are methyl.

67. The poly (allylamine) polymer of claim 56, wherein the alkylene has 6 carbon atoms, hydrophobic alkyl is decyl, and the remaining terminal substituents are methyl.

68. The poly (allylamine) polymer of claim 56, wherein the alkylene has 6 carbon atoms, hydrophobic alkyl is dodecyl, and the remaining terminal substituents are methyl.