MXPA97009565A

MXPA97009565A - Hidrofobo sequestrant containing heteroatomo for the elimination of coleste

Info

Publication number: MXPA97009565A
Application number: MXPA/A/1997/009565A
Authority: MX
Inventors: Stephen Randall Holmesfarley; Harry Mandeville W Iii; S Petersen John
Original assignee: Geltex Pharmaceuticals Inc
Priority date: 1995-06-06
Filing date: 1997-12-04
Publication date: 1998-10-15

Abstract

The present invention relates to a poly (allylamine) polymer and, more generally, to a hydrocarbon amine polymer. Preferably, these polymers are entangled. The present invention also relates to methods for forming these polymers, and methods for their use. In addition, the present invention relates to alkylating agents that can be used to form the polymers, and to the methods or to form the alkylating agents. In general, the polymer scavenger includes a substitute bond for an amine of the polymer. The substitute includes a quaternary amine containing part having one, two or three terminal hydrophobic substitutes. A method for preparing alkylating agents containing quaternary amine, which includes reacting a non-symmetrical dihalide with a tertiary amine having at least one hydrophobic substitute. A method for binding bile dehydrogen salts in a mammal, including administering to the mammal a therapeutically effective amount of the polymer scavenger

Description

HYDROPROPHIC SEQUESTER CONTAINING HETEROATOMO FOR THE ELIMINATION OF CHOLESTEROL Related Requests This is a continuation-in-part of the application Serial No. 08 / 469,659, filed on June 6, 1995, which is a continuation-in-part of the application Serial No. 08 / 258,431, registered on the June 10, 1994, and of the application Serial No. 08 / 332,096, registered on October 31, 1994, incorporating here the guidelines of all of them as a reference in its entirety.

BACKGROUND OF THE INVENTION The salts of bile acids act as detergents to solubilize and consequently favor the digestion of fats in the diet. Bile acids are derived from cholesterol and therefore, the elimination of bile acids can result in the reduction of cholesterol. Following digestion, bile acids can be absorbed passively into the jejunum, or reabsorbed by active transport in the ileum. Bile acids that are not reabsorbed are lost. The reabsorption of bile acids from the intestine preserves lipoprotein cholesterol in the bloodstream. Conversely, the level of cholesterol in the blood can be reduced by reducing the reabsorption of bile acids.

One method for reducing the amount of bile acids that are reabsorbed is that of oral administration of compounds that sequester bile acids which can not be absorbed. The kidnapped bile acids are then excreted. Many of the bile acid sequestrants, however, do not bind to conjugated primary bile acids, such as conjugated cholic acid, well enough to prevent substantial portions from being reabsorbed. In addition, the volume of sequestrants that can be ingested is limited. As a result, the effectiveness of many sequestrants in lowering blood cholesterol levels is also limited. In addition, the synthesis of many sequestrants may be restricted by the cost and performance of the reaction associated with the preparation of suitable precursors. For example, alkylating agents used to modify polymers can be difficult to prepare. The ability of an alkylating agent to react with a polymer can also limit the effectiveness of the resulting sequestrant. There is, therefore, the need for a sequester and a method that resolves or reduces the aforementioned problems.

SUMMARY OF THE INVENTION The present invention relates to a poly (allylamine) polymer and, more generally, to a hydrocarbon amine polymer. Preferably, these polymers are crosslinked. The present invention also relates to methods of obtaining these polymers and methods for their use. The present invention also relates to alkylating agents that can be used to form the polymers and to methods for obtaining the alkylating agents. In one embodiment, the poly (allylamine) polymer is crosslinked and comprises a substituent attached to an amine of the polymer. The substituent includes a quaternary amine containing radical, wherein the nitrogen of the quaternary amine of the radical is attached to the polymer amine by an alkylene having three or more carbons 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 carbons and the remaining terminal substituents are, each independently, alkyl groups having from 1 to about 5 carbons. The method of obtaining the crosslinked poly (allylamine) polymers includes the reaction of a crosslinked poly (allylamine) with a quaternary amine containing compound having the formula R X- (CH2) n N + - R R where R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining ones, each independently, from 1 to about 5 carbons, n is an integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter ion. In another embodiment, the present invention relates to a hydrocarbon amine polymer that includes a substituent attached to a polymer amine. The substituent includes a quaternary amine containing radical, wherein the nitrogen of the quaternary amine of said radical is attached to the amine of the polymer by an alkylene having 3 or more carbons and where at least 2 of the 3 terminal substituents of the quaternary amine they are each a hydrophobic alkyl group having from 6 to about 24 carbons and the other terminal substituent is an alkyl group having from 1 to approximately 5 carbons. The method of obtaining a crosslinked amine hydrocarbon polymer of the invention includes the step of reacting a crosslinked amine hydrocarbon polymer with a quaternary ammonium compound having the formula R X- (CH2) n - N + - R R where R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining ones, each independently, from 1 to about 5 carbons, n is an integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter-ion. The methods of using the poly (allylamine) polymer and hydrocarbon amine polymers of the invention include orally administering it to a mammal in a therapeutic amount to bind salts. biliary, reduce blood cholesterol, treat atherosclerosis, treat hypercholesterolemia or reduce the plasma lipid content of the mammal. In another embodiment, the invention is a quaternary ammonium compound having the formula R X- (CH2) n - N + - RI Y - R where R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining ones, each independently, from 1 to about 5 carbons, n is an integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter-ion. A method of obtaining a quaternary ammonium compound includes the reaction step of a tertiary amine, which has the formula R N - R R wherein, R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining have, each independently, from 1 to about 5 carbons, with an asymmetric dihalide having the formula X1 - (CH2) n - X2 where X1 is chloride, X2 is bromide, and n is an integer with a value of 3 or more.

This invention has many advantages. For example, the poly (allylamine) and hydrocarbon amine polymer sequestrants of the invention bind to conjugated bile acids, which include primary bile acids, which would otherwise be reabsorbed by active transport. One possible The explanation for the improved behavior of the polymeric sequestrants of the invention in terms of binding to bile acids could be their ability to form both hydrogen bonds and ionic bonds with bile acids. The hydrogen bonds can be formed by the secondary amine component of the polymer, while the ionic bonds can be formed by the quaternary amine substituent. In addition, the external, or terminal, distribution of hydrophobic components of the polymer sequestrants with respect to the polymer backbone and with respect to the secondary and quaternary amine components of the polymer can contribute to significantly increase the effectiveness of each given dose of sequestrant. Additionally, the presence of two or more hydrophobic alkyl groups as terminal substituents has the advantage of providing more hydrophobic binding sites of the bile salts. The method of obtaining the polymeric sequestrant of the invention also offers several advantages. For example, alkylation of an amine component of a hydrocarbon amine polymer, such as a poly (allylamine) polymer, with a quaternary amine can be facilitated by the use of a quaternary amine that is reactive with the amine component in the carbon bearing the leaving group which is separated by at least three carbon atoms from the center of quaternary ammonium. It is also believed that the behavior of The resulting sequestrant can be improved by using an alkylene group of at least three carbons to link the quaternary amine to an amine of the hydrocarbon polymer amine, and in particular to a poly (allylamine) polymer. The use of asymmetric dihalides in the preparation of the quaternary amine containing alkylating agents of the present invention can result in a higher yield and purity of the desired product. Since the halogens of an asymmetric dihalide are not equivalent in terms of reactivity, it will be the carbon that carries the most reactive halogen that reacts almost exclusively, thus giving rise to a relatively pure compound with good performance. This relatively pure quaternary amine containing alkylating agent can then be used to alkylate an amine nitrogen of the hydrocarbon polymer amine backbone.

DETAILED DESCRIPTION OF THE INVENTION The features and other details of the invention that will be set forth in the claims will be described in more detail below. It is to be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The main features of this invention can be applied to various embodiments without deviating 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. Preferably, the amine hydrocarbon polymer is crosslinked. More preferably, the hydrocarbon amine polymer is a poly (allylamine) polymer. More preferably, the hydrocarbon amine polymer is a crosslinked poly (allylamine) polymer. Other examples of suitable amine hydrocarbon polymers include poly (vinylamine) and poly (ethylenimine) polymers. The polymer hydrocarbon amine scavenger of the invention includes a substituent attached to an amine of the polymer. The substituent includes a quaternary amine radical, wherein the nitrogen of the quaternary amine of said radical is attached to the amine of the polymer backbone by an alkylene having three or more carbons. At least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having from 6 to about 24 carbons. The remaining terminal substituents are, each independently, alkyl groups having from 1 to about 5 carbons. The term "terminal substituent" of the quaternary amine, as used herein, refers to any of the three substituents on the nitrogen of the quaternary amine which does not be the carbon chain between the amine on the polymer skeleton and the amine of the quaternary ammonium center. The term "hydrophobic alkyl group", as used herein, is an alkyl group having from 6 to about 24 carbons and ending in a hydrophobic moiety. The hydrophobic alkyl group can be, for example, an aliphatic, aromatic, branched chain or cyclic carbon chain. The hydrophobic substituent does not include the alkylene between the nitrogen of the amine polymer backbone and the nitrogen of the quaternary ammonium center. In one embodiment, the hydrocarbon amine polymer is a crosslinked poly (allylamine) polymer and comprises a substituent attached to an amine of the polymer. The substituent includes a quaternary amine containing radical, wherein the nitrogen of the quaternary amine is attached to the polymer amine by an alkylene having 3 or more carbons and wherein at least one of three terminal substituents of the quaternary amine is an alkyl group hydrophobic having from 6 to about 24 carbons. The remaining terminal substituents are, each independently, alkyl groups having from 1 to about 5 carbons. Preferred embodiments include a crosslinked poly (allylamine) polymer where the alkylene has a length of 3 carbons, at least 1 of the 3 terminal substituents of the quaternary amine is a hydrophobic alkyl group which is octyl, decyl, or dodecyl group and the remaining terminal substituents are methyl groups. Other preferred embodiments include a crosslinked poly (allylamine) polymer where the alkylene has a length of 4 carbons, at least 1 of the 3 terminal substituents of the quaternary amine is a hydrophobic alkyl group which is an octyl, decyl or dodecyl group and the remaining substituents are methyl groups. Other preferred embodiments include crosslinked poly (allylamine) polymer where the alkylene has a length of 5 carbons, at least 1 of the 3 terminal substituents of the quaternary amine is a hydrophobic alkyl group which is octyl group, decyl or dodecyl and the remaining terminal substituents are methyl groups. Still other preferred embodiments include a crosslinked poly (allylamine) polymer where the alkylene has a length of 6 carbons, at least 1 of the 3 terminal substituents of the quaternary amine is a hydrophobic alkyl group which is octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. In one embodiment, the poly (allylamine) polymer of the invention has the following general formula - (CH, - CH) - CH, NH (CH2 R - N + - RIR where, n has a value of 3 or more, and R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining ones, each independently, from 1 to about 5. carbons. The method for obtaining crosslinked poly (allylamine) polymers includes the reaction of a crosslinked poly (allylamine) with a quaternary amine containing compound having the formula X - (CH2) n - N + - RIR where, R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining ones, each independently, from 1 to about 5 carbons, n is a integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter-ion. Preferred embodiments of the crosslinked poly (allylamine) obtained by this method include a cross-linked poly (allylamine) polymer. wherein the alkylene is 3 carbons in length, at least 1 of the 3 terminal substituents of the quaternary amine is a hydrophobic alkyl group which is octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Other preferred embodiments of the crosslinked poly (allylamine) prepared by this method include a crosslinked poly (allylamine) polymer in which the alkylene is 4 carbons in length, at least 1 of the 3 substituents Terminals of the quaternary amine is a hydrophobic alkyl group which is octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Additional preferred embodiments of the cross-linked poly (allylamine) obtained by this method include a crosslinked poly (allylamine) polymer in which the alkylene has a length of 5 carbons, at least 1 of the 3 terminal substituents of the Quaternary amine is a hydrophobic alkyl group which is octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Still other preferred embodiments of the crosslinked poly (allylamine) obtained by this method include a crosslinked poly (allylamine) polymer where the alkylene has a length of 6 carbons, at least 1 of the 3 terminal substituents of the quaternary amine is a hydrophobic alkyl group which is octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. In another embodiment, the present invention relates to a hydrocarbon amine polymer that includes a substituent attached to an amine of the polymer. The substituent includes a quaternary amine containing radical, wherein the nitrogen of the quaternary amine of said radical is attached to the polymer amine by an alkylene having 3 or more carbons and wherein at least 2 or the 3 terminal substituents of the quaternary amine are each a hydrophobic alkyl group having from 6 to about 24 carbons. In the case where 2 of the 3 terminal substituents of the quaternary amine are each a hydrophobic alkyl group, the other terminal substituent is an alkyl group having 1 to about 5 carbons. In a preferred embodiment, the hydrocarbon amine polymer is crosslinked. The method of obtaining a crosslinked amine hydrocarbon polymer of the invention includes the step of reacting a crosslinked amine hydrocarbon polymer with a quaternary ammonium compound having the formula R X - (CH2) n - N + - RI Y - R where, R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining ones, each independently, from 1 to about 5 carbons, n is an integer that has a value of 3 or more, X is a leaving group, and Y is a negatively charged counter ion. Preferred embodiments of the crosslinked hydrocarbon amine polymer obtained by this method include poly (vinylamine), poly (allylamine) and poly (ethylene imine) polymers.

The methods of use of the poly (allylamine) polymers and hydrocarbon amine polymers of the invention include oral administration to a mammal in a therapeutic amount to bind bile salts, reduce blood cholesterol, treat atherosclerosis, treat hypercholesterolemia or reduce the plasma lipid content of a mammal.

Generally, a therapeutic amount of the amine hydrocarbon polymers or poly (allylamine) polymers, is an amount that is in a range of about 0.1 grams / day to about 20 grams / day. In one embodiment, the method of the invention is a method of binding bile salts in a mammal, comprising the step of orally administering a therapeutic amount of the amine hydrocarbon polymer of the invention to the mammal. In another embodiment, the method of the invention is a method of binding bile salts in a mammal, comprising the step of orally administering a therapeutic amount of the poly (allylamine) polymer of the present invention to the mammal.

In another embodiment, the invention is a method for reducing blood cholesterol in a mammal, comprising the step of administering to the mammal a therapeutic amount of the hydrocarbon amine polymer, preferably a crosslinked poly (allylamine) polymer, of the invention. In yet another embodiment, the invention includes a method of treating atherosclerosis of a mammal, comprising the step of administering to the mammal a therapeutic amount of the hydrocarbon amine polymer, preferably a cross-linked poly (allylamine) polymer, of the invention. In yet another embodiment, the method of the invention is that of the treatment of hypercholesterolemia in a mammal, comprising the step of administering to the mammal a therapeutic amount of the hydrocarbon polymer amine, preferably a crosslinked poly (allylamine) polymer, of the invention. Another embodiment of the invention is a method for reducing the plasma lipid content of a mammal, comprising the stage of oral administration of a polymer of the invention to the mammal to firmly sequester the conjugated bile acids secreted by the mammal, with what a substantial portion of the conjugated bile acids are excreted by the mammal, and in this way the lipid metabolism is accelerated and as a consequence the plasma lipid content of the mammal is reduced. In an embodiment Preferred, conjugated conjugated primary bile acids include conjugated primary bile acids, such as conjugated cholic acid and conjugated chenodeoxycholic acid. The amine hydrocarbon polymers and poly (allylamine) polymers of this invention are particularly suitable for binding to conjugated primary bile acids, such as glycocholic and glycokenedeoxycholic acids, in mammals, by oral administration of the polymer. A particularly suitable form for oral administration of the hydrocarbon polymer amine and poly (allylamine) polymer is by the formation of a gel in the stomach of the patient. Examples of suitable methods by which the preferred amine polymer of the invention can be formed are those shown below: 1. A method comprising the polymerization of an amine monomer to form a homopolymer. Examples of this method include polymerization of allylamine, ethyleneimine, vinylamine, 1,2-diaminoethene, aminopropyl acrylate, or p-aminomethylstyrene, to form their respective homopolymers. 2. Another method comprises the copolymerization of an amine monomer with one or more additional monomers. These additional 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 still comprises the polymerization of a non-amine monomer to form a homopolymer which is then chemically modified to form an amine polymer. Examples of this method 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 would then be chemically altered to form an amine polymer using reactions such as hydrolysis, nucleophilic substitution, or reduction. The first four homopolymers listed above would then be made poly (vinylamine) and the last four would be made poly (allylamine). It is to be understood that not all of the initial non-amine monomers need to be chemically altered, resulting in an amine polymer that contains part of the initial non-amine monomers in a non-amine state. 4. A fourth method involves the copolymerization of a non-amine monomer with one or more additional monomers. These additional monomers could include amine monomers, such as those listed in the first method, and non-amine monomers, such as those listed in the third method. The copolymer The resultant would then be chemically altered to form an amine polymer as in the third method. Examples could include the copolymerization of acrylamide and styrene, followed by reduction to form copoly (allylamine / styrene), copolymerization of acrylonitrile and vinyl formamide, followed by reduction and hydrolysis, to form copoly (allylamine / vinylamine), and copolymerization of acrylonitrile and allylamine, followed by reduction, to form poly (allylamine). It should be noted that not all of the initial non-amine monomer will be altered chemically, resulting in an amine polymer that contains some of the initial non-amine monomers in a non-amine state.

. A fifth method comprises the formation of an amine polymer through a condensation mechanism. Examples of this method may include the reaction of diethylenetriamine and epichlorohydrin, 1,3-dibromopropane and ethylenediamine, spermine and diglycidyl ether of 1,4-butanediol, or tris (2-aminoethyl) amine and 1, 10-dibromodecane. Each of these amine polymers typically has a molecular weight greater than 2,000. Examples of suitable resulting amine hydrocarbon polymers include poly (vinylamine), poly (allylamine), and poly (ethyleneimine) polymers. The preferred hydrocarbon amine polymer is poly (allylamine) polymer.

Preferably, the hydrocarbon amine polymer is crosslinked, for example, by reaction of the polymer with a suitable crosslinking agent. Examples of suitable crosslinking agents include acryloyl chloride, epichlorohydrin, diglycidyl ether of butanediol, diglycidyl ether of ethanediol, dimethyl succinate, etc. Epichlorohydrin is a preferred crosslinking agent. Typically, the amount of crosslinking agent that is reacted with the hydrocarbon amine polymer is sufficient to provide between about 0.5 and 20 percent of the available spots for reaction with the crosslinking agent. In a preferred embodiment, between about 0.5 and 6 percent of the amine groups of a hydrocarbon amine polymer react with the crosslinking agent. In another preferred embodiment, between about 2 and about 12 percent of the amine groups of a hydrocarbon amine polymer react with the crosslinking agent. The crosslinking of the polymer can be achieved by reacting the polymer with a suitable crosslinking agent in an aqueous solution at about 25 ° C for a period of time of about 18 hours to thereby form a gel. The gel is then combined with water or dried to form a particulate solid. The particulate solid can then be washed with water and dried under suitable conditions, such as a temperature of about 50 ° C for a period of time of about 18 hours. The hydrocarbon amine polymer can be alkylated to form the sequestrants of the invention. The term "alkylating agent", as used herein, refers to a reagent which, when reacted with a hydrocarbon amine polymer, causes the nitrogen atom of the quaternary amine-containing radical to be covalently attached to one or more amines of the skeleton of the hydrocarbon amine polymer by an alkylene having 3 or more carbon atoms. Among the suitable alkylating agents of the present invention are quaternary ammonium compounds. Therefore, another embodiment of the invention is a quaternary ammonium compound having the formula R X- (CH2) n - N + - R R where R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining ones, each independently, from 1 to about 5 carbons, n is an integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter ion. In one embodiment, X is a halide. Preferably, the value of n is in a range of 3 to 6. In other embodiments, one or two of said alkyl groups is a methyl group. Particular examples of quaternary ammonium compounds suitable as alkylating agents include the following: (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) decyldimethylammonium bromide; (3-chloropropyl) decyldimethylammonium bromide; (5-tosylpentyl) dodecyldimethylammonium bromide; (6-bromohexyl) octyldimethylammonium bromide; (12-bromododecyl) decyldimethylammonium bromide; (3-bromopropyl) tridecylammonium bromide; (3-bromopropyl) docosyldimethylammonium bromide; (6-bromohexyl) docosyldimethylammonium bromide; (4-chlorobutyl) dodecyldimethylammonium bromide; (3-chloropropyl) octadecyldimethylammonium bromide; (3-chloropropyl) -silyldimethylammonium bromide; (3-chloropropyl) methyldioctylammonium bromide; (3-chloropropyl) methyldidecylammonium bromide; (3-chloropropyl) cyclohexyldimethylammonium bromide; (3-chloropropyl) tetradecyldimethylammonium bromide; etc. It is to be understood that the above compounds can be employed in halogenated forms including bromides, chlorides and iodides as well as other negatively charged ions such as acetate, nitrate, sulfate, p-toluenesulfonate, etc. An example of a suitable method by which the preferred quaternary ammonium compounds, useful as alkylating agents of the invention, can be obtained includes the reaction steps of a tertiary amine, which has the formula R I N - R I R where R represents an alkyl group, at least one of which has from 6 to about 24 carbons, and the remaining ones, each independently, from 1 to about 5 carbons, with an asymmetric dihalide having the formula X1 - (CH2) n - X2 where X1 is chloride X2 is bromide, and n is an integer with a value of 3 or greater. In other embodiments, the tertiary amine can have 2 or 3 alkyl or substituted alkyl groups of 6 to about 24 carbons. In the case of having 2, the remaining alkyl group has from 1 to about 5 carbons.

Typically, the alkylation is carried out by combining the substituted tertiary amine with a suitable dihalide in an organic solvent. An example of a suitable symmetrical dihalide is a dichloride. An example of preferred dichloride is 1,3-dichloropropane. Preferred dihalides of this invention also include asymmetric dihalides. The term "asymmetric dihalides", as used herein, refers to those dihalides in which the halides of the dihalide are not the same and consequently not they have the same reactivity as alkylating agents. Suitable examples of asymmetric dihalides include 1-bromo-3-chloropropane and 1-bromo-4-chlorobutane. Typically, when the dihalide is a bromide / chloride combination, the end of the molecule carrying the bromide is more reactive than the end of the molecule that carries the chloride. According to this, the reaction of the asymmetric dihalide can give rise to an almost exclusive reaction at the end carrying the bromide and leave the end of the chloride unreacted. This relatively pure compound can then be used to alkylate the nitrogen of the hydrocarbon amine polymer, with the reaction occurring at the chloride end. The use of asymmetric dihalides increases both the yield and the purity of the resulting quaternary amine-containing alkylating agents, by avoidance of undesirable side reactions which normally occur using symmetrical dihalides. Examples of suitable organic solvents include methanol, diethyl ether, etc. A preferred organic solvent is methanol. The reaction is maintained at a temperature and for a period of time sufficient to allow the reaction of the tertiary amine with the asymmetric dihalide. These parameters are typically dependent on the nature of the reagents and can be determined by one skilled in the art with only routine experimentation.

The reaction ends by removal of the solvent by suitable methods. The alkylating agent containing crude quaternary amine is prepared for further reaction by methods known to those skilled in the art. The hydrocarbon amine polymer is typically alkylated by combining the polymer with the alkylating agent containing quaternary amine in an organic solvent or water. The amount of the alkylating agent combined with the hydrocarbon amine polymer is generally sufficient for the reaction of the alkylating agent to take place with more than about 5 percent reactive nitrogens on the amine hydrocarbon polymer. Examples of suitable solvents include methanol, ethanol, acetonitrile, water, etc. The preferred solvents are water and methanol. In a particularly preferred embodiment of the invention, the hydrocarbon amine polymer is a crosslinked poly (allylamine), wherein the substituent includes (3-propyl) dodecyldimethylammonium chloride. Alternatively, the hydrocarbon amine polymer is a crosslinked poly (allylamine), wherein the substituent includes butyldioctylmethylammonium chloride. In addition, the particular preferred crosslinked poly (allylamine) is crosslinked by epichlorohydrin which is present in a range of t 1/2 to t 6 percent of the amines of the polymer.

The hydrocarbon amine polymer of the invention can be subsequently treated or combined with other materials to form a composition for oral administration of the hydrocarbon amine polymer. The present pharmaceutical compositions are generally prepared by known procedures using well-known and readily available ingredients. In the preparation of the compositions of the present invention, the hydrocarbon amine polymer can be present alone, can be mixed with a vehicle, diluted with a vehicle, or within a support that can be in the form of a capsule, sachet, paper or another wrap. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the polymer. In this way, the compositions may be in the form of tablets, pills, powders, rhombuses, sachets, wafers, elixirs, suspensions, syrups, aerosols (in the form of solid or in a liquid medium), soft or hard gelatin capsules, powders sterile packed, and the like. Examples of suitable carriers, excipients and diluents include foods, beverages, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, methylhydroxybenzoates, polyhydroxybenzoates, and talc. As the negatively charged counter ion of the pharmaceutical composition, organic ions, inorganic ions or combinations thereof may be mentioned. Suitable inorganic ions for use in this invention include halide (especially chloride), carbonate and bicarbonate. Suitable organic ions include acetate and benzoate. The invention will be described in more detail and in more detail with the following examples. All parts and percentages are by weight unless otherwise specified.

Example 1: Preparation of poly (allylamine) hydrochloride crosslinked with epichlorohydrin To a 5 gallon (19 liter) vessel was added poly (allylamine) hydrochloride (1 kg), obtained from Nitto Boseki, and water (4 liters). The mixture was stirred to dissolve the hydrochloride and the pH adjusted by addition of solid NaOH (284 grams). The resulting solution was cooled to room temperature, after which the cross-linking agent epichlorohydrin (50 ml) was added all at once with stirring. The resulting mixture was gently stirred until it gelled (approximately 35 minutes). The crosslinking reaction was allowed to proceed for an additional 18 hours at room temperature environment, after which the polymer gel was separated and placed in portions in a mixer with a total of 10 liters of water. Each portion was mixed gently for about three minutes to form coarse particles which were then stirred for 1 hour and collected by filtration. The solid was rinsed three times by suspending it in water (10 liters, 15 liters, 20 liters), stirring each suspension for 1 hour, and collecting the solid each time by filtration. The resulting solid was then rinsed once by suspending it in isopropanol (17 liters), the mixture was stirred for 1 hour, and the solid was then collected by filtration, after which the solid was dried in a vacuum oven at 50 ° C for 18 hours to give approximately 677 grams of the cross-linked polymer as a granular, white, brittle solid.

Example 2: Alkylation of crosslinked poly (allylamine) with (3-bromopropyl) dodecyldimethylammonium bromide. The crosslinked poly (allylamine) was obtained as set forth in Example 1. Crosslinked poly (allylamine) (12) was added to a flask. 5 grams, 6% crosslinked, crushed to less than 30 mesh), (3-bromopropyl) -dodecyldimethylammonium bromide (17.5 grams, obtained by reaction of 1,3-dibromopropane and N, N-dimethyl-1-aminododecane in diethyl ether), and methanol (334 ml). The mixture was heated to 65 ° C with stirring.

Upon reaching 65 ° C, aqueous sodium hydroxide (1.14 grams of 50% solution) was added and stirring was continued at 65 ° C for 2 hours. Two additional aliquots of aqueous sodium hydroxide (1.14 grams of 50% solution) were added sequentially and stirring was continued at 65 ° C for an additional 2 hours for each aliquot. Aqueous sodium hydroxide (1.14 grams of 50% solution) was then added and stirring was continued at 65 ° C for an additional 12 hours. The mixture was then allowed to cool to room temperature. The solid product was filtered and washed by suspension, stirring for 30 minutes, and filtering from the following fluids: 1. 459 ml of 2 M NaCl (aqueous) 2. 459 ml of 2 M NaCl (aqueous) 3. 2 1 deionized water 4. 2 1 deionized water 5. 2 1 deionized water 6. 2 1 deionized water The solid was then dried in an oven with air draft at 60 ° C to give 17.4 grams of an off-white solid. The solid was then ground and passed through an 80 mesh screen.

Example 3: Alkylation of crosslinked poly (allylamine) with (3-bromopropyl) dodecyldimethylammonium bromide Crosslinked poly (allylamine) was obtained in the manner set forth in Example 1. To a flask was added the crosslinked poly (allylamine) (12.5 grams, 6% crosslinking, crushed to less than 30 mesh), (3-bromopropyl) -dodecyldimethylammonium bromide (35 grams, obtained by reaction of 1,3-dibromopropane and N, N-dimethyl-l-aminododecane in diethyl ether ), and methanol (334 ml). The mixture was heated to 65 ° C with stirring. Upon reaching 65 ° C, aqueous sodium hydroxide (1.99 grams of 50% solution) was added and stirring was continued at 65 ° C for 2 hours. Two additional aliquots of aqueous sodium hydroxide (1.99 grams of 50% solution) were added sequentially and stirring was continued at 65 ° C for a further 2 hours for each aliquot. Aqueous sodium hydroxide (1.99 grams of 50% solution) was then added and stirring was continued at 65 ° C for an additional 12 hours. The mixture was then allowed to cool to room temperature. The solid product was filtered and washed by suspension, stirring for 30 minutes and filtering from the following fluids 1. 459 ml of 2 M NaCl (aqueous) 2. 459 ml of 2 M NaCl (aqueous) 3. 2 1 deionized water 4. 2 1 deionized water 5. 2 1 deionized water 6. 2 1 deionized water The solid was then dried in a drying oven with air draft at 60 ° C to give 25.6 grams of a whitish solid. The solid was then ground and passed through an 80 mesh screen.

Example 4: Alkylation of poly (allylamine) crosslinked with (3-bromopropyl) dodecyldimethylammonium bromide Crosslinked poly (allylamine) was obtained following the method of Example 1 except that 16.7 ml of epichlorohydrin was used instead of 50 ml. To a flask was added crosslinked poly (allylamine) (12.5 grams, 2% crosslinking, crushed to less than 30 mesh), (3-bromopropyl) -dodecyldimethylammonium bromide (140.8 grams, obtained by reaction of 1, 3-dibromopropane and N, N-dimethyl-l-aminododecane in diethyl ether), and methanol (334 ml). The mixture was heated to 65 ° C with stirring. Upon reaching 65 ° C, aqueous sodium hydroxide (7.1 grams of 50% solution) was added sequentially and stirring was continued at 65 ° C for an additional 2 hours Two additional aliquots of aqueous sodium hydroxide were added sequentially ( 7.1 grams of 50% solution) and stirring continued at 65 ° C for 2 more hours for each aliquot. Aqueous sodium hydroxide (7.1 grams of 50% solution) was added and stirring was continued at 65 ° C for an additional 12 hours. The mixture was then allowed to cool to room temperature. The solid product was filtered and washed by suspension, stirring for 30 minutes and filtering from the following fluids 1. 1.7 1 2M NaCl (aqueous) 2. 1.7 1 2M NaCl (aqueous) 3. 8 1 deionized water 4. 8 1 deionized water 5. 8 1 deionized water 6. 8 1 deionized water 7. 4 1 deionized water The solid was then dried in a drying oven with air draft at 60 ° C to give 39.8 grams of a whitish solid. The solid was then ground and passed through an 80 mesh screen.

Example 5: Alkylation of crosslinked poly (allylamine) with (3-bromopropyl) octyldimethylammonium bromide Crosslinked poly (allylamine) was obtained following the method set forth in Example 1. To a flask were added crosslinked poly (allylamine) (12.5 grams, 2% crosslinking, crushed to less than 30 mesh), (3-bromopropyl) -octyldimethylammonium bromide (30.2 grams, obtained by reaction of 1,3-dibromopropane and N , N-dimethyl-l-aminooctane in diethyl ether), and methanol (334 ml). The mixture was heated to 65 ° C with stirring. Upon reaching 65 ° C, aqueous sodium hydroxide (2.0 grams of 50% solution) was added and stirring was continued at 65 ° C for 2 hours. Two additional aliquots of aqueous sodium hydroxide (2.0 grams of 50% solution) were added sequentially and stirring was continued at 65 ° C for a further 2 hours for each aliquot. Aqueous sodium hydroxide (2.0 grams of 50% solution) was then added and stirring was continued at 65 ° C for an additional 12 hours. The mixture was then allowed to cool to room temperature. The solid product was filtered and washed by suspension, stirring for 30 minutes and filtering from the following fluids 1. 800 ml of 2 M NaCl (aqueous) 2. 800 ml of 2 M NaCl (aqueous) 3. 2 1 of deionized water 4. 2 1 deionized water 5. 1 1 deionized water The solid was then dried in a drying oven at 60 ° C to give 16.8 grams of an off-white solid. He solid was crushed and passed through an 80 mesh screen.

Example 6: Alkylation of crosslinked poly (allylamine) with (6-bromohexyl) octyldimethylammonium bromide Crosslinked poly (allylamine) was obtained following the method set forth in Example 1. Crosslinked poly (allylamine) (12.5 grams) was added to a flask. 6% crosslinking, crushed to less than 30 mesh), (6-bromohexyl) -octyldimethylammonium bromide (33.7 grams, obtained by reaction of 1,6-dibromohexane and N, N-dimethyl-1-aminooctane in ether diethyl), and methanol (334 ml). The mixture was heated to 65 ° C with stirring. Upon reaching 65 ° C, aqueous sodium hydroxide (1.68 grams of 50% solution) was added and stirring was continued at 65 ° C for 2 hours. Two additional aliquots of aqueous sodium hydroxide (1.68 grams of 50% solution) were added sequentially and stirring was continued at 65 ° C for a further 2 hours for each aliquot. Aqueous sodium hydroxide (1.68 grams of 50% solution) was then added and stirring was continued at 65 ° C for an additional 12 hours. The mixture was then allowed to cool to room temperature. The solid product was filtered and washed by suspension, stirring for 30 minutes and filtering from the following fluids 1. 1 1 of 2 M NaCl (aqueous) 2. 1 1 of 2 M NaCl (aqueous). 3. 1 1 of repeated deionized water until the conductivity of the solution was less than .1 mS / cm. The solid was then dried in an air-drying oven at 60 ° C to give 15.7 grams of an off-white solid. The solid was crushed and passed through an 80 mesh screen.

Example 7: Alkylation of crosslinked poly (allylamine) with (4-bromobutyl) dioctylmethylammonium bromide Crosslinked poly (allylamine) was obtained following the method set forth in Example 1, with the exception that 25 ml of crosslinking agent epichlorohydrin was used in place of 50 mi. To a flask were added crosslinked poly (allylamine) (12.5 grams, 3% crosslinked, crushed to less than 30 mesh), (4-bromobutyl) -dioctylmethylammonium bromide (65.8 grams (crude)) obtained by reaction of 1,4-dibromobutane and N, N-dioctylmethylamine in methanol), and methanol (334 ml). The mixture was heated to 65 ° C with stirring. Upon reaching 65 ° C, aqueous sodium hydroxide (3.28 grams of 50% solution) was added and stirring was continued at 65 ° C for 2 hours. Two additional aliquots of aqueous sodium hydroxide (3.28 grams of 50% solution) were added sequentially and the Stir at 65 ° C for 2 more hours for each aliquot. Aqueous sodium hydroxide (3, 28 grams of 50% solution) and stirring was continued at 65 ° C for an additional 12 hours. The mixture was then allowed to cool to room temperature. The solid product was filtered and washed by suspension, stirring for 30 minutes and filtering from the following fluids 1. 800 ml of methanol 2. 1000 ml of methanol 3. 890 ml of 2 M NaCl (aqueous) 4. 890 ml of NaCl 2 M (aqueous) 5. 2 1 deionized water 6. 2 1 deionized water The solid was then dried in an air draft oven at 60 ° C to give 27.1 grams of an off-white solid. The solid was then crushed and passed through an 80 mesh screen.

Example 8: Preparation of (3-chloropropyl) -dodecyldiethyl ammonium bromide A three-neck, two-liter, round-bottomed flask equipped with an air cooler and stirring magnetic plate was charged with N, N-dimethyldodecylamine ( 297.24 grams, 1.40 moles), l-bromo-3-chloropropane (220.44 grams, 1.40 moles) and methanol (250 ml). The reaction was maintained at 65 ° C for 24 hours. The methanol was removed by rotary evaporation under reduced pressure to give a brown slurry. Methyl-tert-butyl ether (2 liters) was added to the sludge, which resulted in the formation of a white solid. The mixture was stirred for two hours and a white solid in semi-crystalline particles was collected by vacuum filtration. The particles were dried in a vacuum oven at 35 ° C for 24 hours. The yield was 228.2 grams (0.61 moles, 44%).

Example 9: Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) dodecyldimethylammonium bromide A cross-linked poly (allylamine) was obtained as set out in Example 1, with the exception that the final crosslinking was 3% in moles To a 3-neck flask of 2 liters capacity, equipped with a thermometer and a coolant, poly (allylamine) (25 grams, 3% crosslinking, ground to -10 mesh), (3-chloropropyl) bromide were added. dodecyldimethylammonium (280 g = 0.755 moles); prepared as set forth in Example 8) and water (750 ml). The mixture was heated to 100 ° C with stirring. Upon reaching 100 ° C, aqueous sodium hydroxide (6.1 grams of 50% solution) was added 10 times with the same time spacing between additions over the next 8 hours. Stirring was continued at 100 ° C for an additional 16 hours. The mixture was then allowed to cool to room temperature. Concentrated hydrochloric acid (50 ml) was added, the mixture was stirred for 10 minutes, and the solid was collected by filtration. The solid was washed on the funnel with 1.5 liters of methanol. The solid product was filtered off and washed by suspension, stirring for 30 minutes, and filtering from the following fluids: 1. 1 1 methanol 2. 3.3 1 2M NaCl (aqueous) 3. 3.3 1 2M NaCl (aqueous) 4. 3.3 1 2M NaCl (aqueous) 5.8 1 deionized water The solid was then resuspended in deionized water (4 liters) and the pH was adjusted to 2.2 with HCl. The solid was collected again by filtration (178.6 grams) and then dried in a stove with air draft to give 111 g. The solid was then crushed and passed through 80 mesh screen.

Example 10: Alkylation of poly (allylamine) crosslinked with (3-chloro) propyl-dimethylhexylammonium bromide Example 9 was repeated, using (3-chloro) propyl-dimethylhexylammonium bromide (216.4 g) in place of 3-chloropropyldodecyldimethylammonium bromide. The yield was 85.6 g.

Example 11: Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) dimethylcyclohexyl ammonium bromide Example 9 was repeated, using (3-chloropropyl) -dimethylcyclohexylammonium bromide (213.2 g) instead of (3) -chloropropyl) dodecyldimethylammonium. The yield was 86.4 g.

Example 12: Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) dimethyloctylammonium bromide Example 9 was repeated, using (3-chloropropyl) dimethyloctylammonium bromide (237.7 g) in place of (3-chloropropyl) bromide dodecyldimethylammonium. The yield was 104.6 g- Example 13: Alkylation of poly (allylamine) crosslinked with (3-chloropropyl) dimethyl-amylammonium bromide Example 9 was repeated, using (3-chloropropyl) dimethyl-amylammonium bromide (269.4 g) in Place of (3-chloropropyl) dodecyldimethylammonium bromide. The yield was 101.7 Example 14: Alkylation of crosslinked poly (allylamine) with (3-chloropropyl) dimethyltetradecylammonium bromide Example 9 was repeated, using (3-chloropropyl) dimethyltetradecylammonium bromide (301.2 g) in place of (3-) bromide chloropropyl) dodecyldimethylammonium. The yield was 112.3 g.

Example 15: Alkylation of poly (allylamine) crosslinked with (3-chloropropyl) methyldioctylammonium bromide Example 9 was repeated, using (3-chloropropyl) methyldioctylammonium bromide (272 g) in place of (3-chloropropyl) dodecyldimethylammonium bromide and using 5.5 g of aqueous NaOH in each addition. The yield was 96.8 g.

Example 16: Alkylation of crosslinked poly (allylamine) with (4-chlorobutyl) methyldioctylammonium bromide Example 9 was repeated, using (4-chlorobutyl) methyldioctylammonium bromide (241.6 g) in place of (3-chloropropyl) bromide dodecyldimethylammonium and using 4.4 g of aqueous NaOH in each addition. The yield was 80.0 g.

Example 17: Alkylation of crosslinked poly (allylamine) with (4-chlorobutyl) dimethyldodecylammonium bromide Example 9 was repeated, using (4-chlorobutyl) dimethyldodecylammonium bromide (290.5 g) in place of (3-chloropropyl) bromide dodecyldimethylammonium. The yield was 93.9 g- Example 18: Alkylation of crosslinked poly (allylamine) with (5-chloropentyl) methyldodecylammonium bromide Example 9 was repeated, using (5-chloropentyl) methyldodecylammonium bromide (150.6 g) in place of (3-chloropropyl) bromide dodecyldimethylammonium and using 3.0 g of aqueous NaOH in each addition. The yield was 46.2 g.

Example 19: Alkylation of crosslinked poly (allylamine) with (10-bromodecyl) trimethylammonium bromide Example 9 was repeated, using (10-bromodecyl)) trimethylammonium bromide (271.0 g) in place of (3-chloropropyl bromide Dodecyldimethylammonium. Water was added after 4 hours (100 ml) and again after 8 hours (100 ml). The yield was 101.8 g.

Example 20: Alkylation of crosslinked poly (allylamine) with (6-chlorohexyl) dimethyl-amylammonium bromide Example 9 was repeated, using (6-chlorohexyl)) dimethyl-amylammonium bromide (145.2 g) in place of (3-chloropropyl bromide ) dodecyldimethylammonium and using 3.0 g of aqueous NaOH in each addition. The yield was 46.2 g.

Example 21: Preparation of (4-chlorobutyl) -dimethyldodecylammonium bromide A 1000 ml round bottom flask, equipped with air coolers and magnetic stirring plate, was charged with N, N-dimethyldodecylamine (308.8 grams, 1.45 moles), l-bromo-4-chlorobutane (249.98 grams, 1.45 moles) and 300 ml of methanol. The reaction was maintained at 65 ° C for 48 hours. The solvent was removed by rotary evaporation under reduced pressure to give a brown oil. To the oil was added 100 ml of l-butanol. The mixture was distilled under vacuum between 30 ° C and 50 ° C until the distillate collection was stopped. Yield 384.47 grams (0.99 moles, 69%).

Example 22: Preparation of (2-chloroethyl) dimethyldodecylammonium bromide A 1000 ml round-bottomed flask equipped with air coolers and cooling plate was charged. magnetic stirring, with N, N-dimethyldodecylamine (186.46 grams, 0.875 moles), l-bromo-2-chloroethane (125.6 grams, 0.875 moles) and methanol (150 ml). The reaction was maintained at 65 ° C for 48 hours. The solvent was removed by rotary evaporation under reduced pressure to give a brown oil. The oil was placed in a beaker and stirred with t-butylmethyl ether (2 liters) which resulted in the formation of a brownish white precipitate. The solid was collected by vacuum filtration. The solid was dried in a vacuum oven at 30 ° C overnight. Yield 197.0 grams (0.55 moles, 63%).

Example 23: Comparison of reactivity for quaternary ammonium alkylating agents The alkylating agents were prepared (4-chlorobutyl) dodecyldimethylammonium bromide, (3-chloropropyl) dodecyldimethylammonium bromide and (2-chloroethyl) dodecyldimethylammonium bromide by the method followed in the Examples 21, 8 and 22, respectively. Each alkylating agent was reacted under identical conditions with crosslinked poly (allylamine) as indicated in the procedure of Example 9. The reactivity of each alkylating agent was assessed and compared with the amine of the poly (allylamine) backbone. The following results were obtained: The percentage of alkylation was obtained by elemental analysis. The simple alkylation of each amine would correspond to 100% alkylation; the double alkylation of each amine would correspond to 200% alkylation; triple alkylation each amine would correspond to 300% alkylation. The N / C ratio for the polymer is obtained by elemental analysis. Since the alkylating agent has a different N / C ratio than the base polymer, it is easy to determine the amount of an alkylating agent given that it has to bind to the polymer to change the N / C ratio from that obtained for the starting material to the obtained for the final product. The result is expressed as a percentage of total amines in the polymer that has been alkylated, with numbers greater than 100 percent representing multiple alkylations on a single amine. For example, the N / C ratio obtained for the starting material was 0.313. After alkylation with alkylating agent of n = 3, the N / C ratio became 0.0922, which represents 124% alkylation. This calculation is made using the equation: % alkylated = (3.2 * (N / C) -1) / (1-N / C * 17) where 3.2 is the C / N ratio for the starting material, and 17 is the C / N ratio for the alkylating agent (16 is used in the case of the alkylating agent of n = 2, and 18 in the case of the agent alkylator of n = 4). From these results it follows that the alkylating agent of n = 2 is much less effective in alkylating the amines of the amine polymer than the agents of n = 3 and n = 4. The authors of the present invention support the hypothesis that this effect is due to the influence of the quaternary amine on the reactivity of the alkyl halide group. Therefore, it can be concluded that the use of alkylating agents, when the quaternary amine has more 2 carbon atoms apart from the carbon atom carrying the halogen of the alkyl halide, leads to unexpectedly improved reactivity over that of alkylating agents with 2 carbon atoms or less.

Example 24: Preparation of (3-chloropropyl) cyclohexyldimethylammonium bromide N, N-dimethylcyclohexylamine (210.06 grams) was introduced into a 1-liter capacity three-necked Morton flask equipped with an air cooler and magnetic stirring plate. , 1.65 moles), l-bromo-3-chloropropane (259.99 grams, 1.65 moles) and methanol (250 ml). The reaction was maintained at 65 ° C for 24 hours. Methanol was removed by rotary evaporation under reduced pressure to give a brown slurry. Tert-butylmethyl ether (600 ml) was added to the sludge which resulted in the formation of an oil. The liquid phase of the oil was decanted and a second portion of methyl tert-butyl ether (600 ml) was added. The mixture was stirred and the liquid phase was separated by decanting the thick sludge. Diethyl ether (600 ml) was added to the thick mud. resulted in the formation of a semi-solid, white layer. The mixture was stirred and a liquid phase separated. The white solid was introduced in a vacuum oven at 35 ° C for 24 hours. The yield was 404.9 grams (1.42 moles, 85%).

Example 25: Preparation of (3-chloropropyl) -tetradecyldimethylammonium bromide A 3 liter, 3-neck round bottom flask equipped with air condensers and a magnetic stirring plate, N, N-dimethyltetradecylamine, were added. (311.59 grams, 1.29 moles), l-bromo-3-chloropropane (203.09 grams, 1.29 moles) and methanol (250 ml). The reaction was maintained at 65 ° C for 24 hours. The methanol was removed by rotary evaporation under reduced pressure to give a slurry. Methyl-tert-butyl ether (500 ml) was added to the sludge which resulted in the slow formation of a white solid. The mixture was stirred for half an hour and a particulate solid was collected as white paste by vacuum filtration. The solid was placed in a vacuum oven at 35 ° C for 24 hours. The yield was 420 grams (1.05 moles, 82%).

Example 26: Preparation of (3-chloropropyl) hexyl-dimethylammonium bromide A 500 ml round bottom, 3-necked flask was charged, equipped with air coolants and a magnetic stir plate, with N, N-dimethylhexylamine (199.46 grams, 1.54 moles, l-bromo-3-chloropropane (243.00 grams, 1.54 moles) and 250 ml of methanol The reaction was maintained at 65 ° C for 24 hours The solvent was removed by rotary evaporation under reduced pressure to give a brown viscous oil The yield was 445.8 grams (1.55 moles, 100% ).

Example 27: Preparation of (3-chloropropyl) octyl-dimethylammonium bromide. N, N-dimethyloctylamine was introduced into a 500 ml capacity 3-neck round bottom flask equipped with air coolers and a magnetic stir plate. (110.02 grams, 0.70 moles), l-bromo-3-chloropropane (110.20 grams, 0.70 moles) and methanol (150 ml). The reaction was maintained at 65 ° C for 24 hours. The solvent was removed by rotary evaporation under reduced pressure to give a brown oil. The oil was extracted with methyl tert-butyl ether (600 ml) by mixing them together in a large beaker and separating the excess solvent by decantation. This stage was repeated 3 times. Additionally, the oil was extracted with diethyl ether (600 ml) and the excess solvent was decanted. The viscous oil was dried in a vacuum oven at 35 ° C overnight. The yield was 174.14 grams (0.55 moles, 79%).

Example 28: Preparation of (3-chloropropyl) octadecyldimethylammonium bromide To a 1000 ml round bottom flask equipped with air coolers and a magnetic stir plate was added N, N-dimethyloctadecylamine (301.0 grams, 1.01 moles), l-bromo-3-chloropropane (170.0 grams, 1.08 moles) and methanol (200 ml). The reaction was maintained at 65 ° C for 18 hours. The solvent was removed by rotary evaporation under reduced pressure to give a clear oil. The oil was transferred to a beaker containing methyl ethyl ketone (250 ml) which resulted in the formation of a white precipitate. The solid material was collected by vacuum filtration, resuspended in methyl ethyl ketone (250 ml), and collected by vacuum filtration two additional times. The solid was placed in a vacuum oven at 30 ° C overnight. The yield was 274.9 grams (0.59 moles, 58%).

Example 29: Preparation of (3-chloropropyl) decyl-dimethylammonium bromide N, N-dimethylethylamine (200.0 grams) was introduced into a 1000 ml round bottom flask equipped with air coolers and a magnetic stir plate. , 1.08 moles), l-bromo-3-chloropropane (170 grams, 1.08 moles) and methanol (200 ml). The reaction was maintained at 65 ° C for 18 hours. The solvent was removed by rotary evaporation under reduced pressure and then by vacuum distillation to give a brown oil. The oil was placed in a beaker and stirred with hexane / t-butylmethyl ether solution 1: 1 (400 ml) which caused a white precipitate. The solids were collected by vacuum filtration. The solids were dried in a vacuum oven at 30 ° C overnight. The yield was 305.0 grams (0.089 moles, 82%).

Example 30: Preparation of (3-chloropropyl) -dioctylmethylammonium bromide A 1 liter, three-necked round bottom flask equipped with air coolers and magnetic stirring plate was charged with N, N-dioctylmethylamine ( 202.48 grams, 0.79 moles), l-bromo-3-chloropropane (124.8 grams, 0.79 moles) and methanol (250 ml). The reaction was maintained at 65 ° C for two days. The methanol was removed by rotary evaporation under reduced pressure to give an oil. To the oil was added ethyl methyl ketone (50 ml) and hexane (200 ml) which gave a slow formation of a white solid. The solvent of the mixture was decanted. The remaining solid was washed with hexane (50 ml) twice. The solid was placed in a vacuum oven at 35 ° C for 24 hours. 259 grams of a waxy solid were produced (0.625 moles, 79%).

Example 31: Preparation of (3-chloropropyl) -didecylmethyl ammonium bromide A round-bottomed flask was charged, of three mouths, of 2 liters of capacity, equipped with air coolers and a plate of magnetic stirring, with N, N-didecylmethylamine (65.49 grams, 0.21 moles), l-bromo-3-chloropropane (33 , 06 grams, 0.21 moles) and methanol (250 ml). The reaction was maintained at 65 ° C for 6 days. The methanol was removed by rotary evaporation under reduced pressure to give an oil. To the oil was added hexane (200 ml) which resulted in the slow formation of a white solid. The solvent was removed by decanting the mixture. The remaining solid was dried overnight under vacuum. The yield was 81.67 grams, 0.17 moles, 82%).

Example 32: Preparation of (6-chlorohexyl) -dodecyldimethylammonium bromide To a 500 ml round bottom flask, equipped with air coolers and magnetic stirring, N, N-dimethyldodecylamine (95.13 grams, 0.513 moles) was added, 1-bromo-6-chlorohexane (102.40 grams), 0.513 moles) and tert-butyl methyl ether (200 ml). The reaction was maintained at 58 ° C for 14 hours. During this time a white precipitate formed. The The reaction was cooled to room temperature and tert-butyl methyl ether (350 ml) was added. The solids were collected by vacuum filtration. The mother liquors were then allowed to react at 60 ° C and the solids were collected in a similar manner. The combined solids were dried in a vacuum oven at 35 ° C for 24 hours, which yielded 127.36 grams.

Example 33: Preparation of (4-chlorobutyl) -dioctylmethylammonium bromide To a 500 ml round bottom flask, equipped with air coolers and magnetic stirring, were added N-methyldioctylamine (201.83 grams, 0.790 moles), 1-bromo-4-chlorobutane (135.517 grams, 0.790 moles) and methanol (250 ml). The reaction was maintained at 68 ° C for 48 hours. The reaction was cooled to room temperature. The solvent was removed by rotary evaporation until a thick oil remained. The solvent was continued to be removed under high vacuum at 50 ° C, which led to the production of 333.53 grams of a thick brown oil.

Example 34: Preparation of (5-chloropentyl) -dodecyldimethylammonium bromide To a 500 liter round-bottomed flask equipped with air coolers and magnetic stirring, they added N, N-dimethyldodecylamine (230.17 grams, 1.078 moles), l-bromo-5-chloropentane (199.77 grams, 1.076 moles) and tert-butyl methyl ether (250 ml). After 2 hours of heating at 60 ° C, the reaction became thick and white and a precipitate formed. Additional tert-butylmethyl ether (250 ml) was added. The reaction was maintained at 60 ° C for 24 hours. The reaction was cooled to room temperature and the solid was collected by vacuum filtration. The solids were dried in a vacuum oven at 35 ° C for 24 hours, which led to 207.40 grams.

Example 35: Preparation of crosslinked poly (vinylamine); alkylation of poly (vinylamine) crosslinked with (3-chloropropyl) dimethyldodecylammonium bromide Poly (vinylamine) free base (molecular weight = 40,000; Air Products; 62.5 g) was dissolved in water (188 ml) and methanol (250 ml) . Epichlorohydrin (2.8 g) was added and the mixture was stirred until gelled. The gel was broken and suspended in water (13 1).

The solid was collected by filtration and dried in an oven with air draft at 60 ° C to give 75.2 g of solid. This solid was crushed and passed through a 10 mesh sieve. The crushed solid (14.8 grams) was reacted in a similar manner to Example 9, using 140 g of (3-chloropropyl) -dimethyldodecylammonium bromide and 30 grams of aqueous base, which yielded 57.7 g of product.

Comparison of efficacy of Examples 10, 12, 13 and 19 Examples 10, 12, 13 and 19 were obtained starting from the alkylating agents of the formula: CH, Polymer - (CH2) n - N + - (CH2) m - H CH, where you have the following: Examples 10, 12 and 13 are examples of the present invention, which include a terminal hydrophobic alkyl group. The hydrophobic alkyl group has a chain length of 6 in Example 10, 8 in Example 12 and 10 in Example 13. The hydrocarbon chain (n = 10) of Example 19 is not considered to be a terminal hydrophobic group anymore. which is attached to the quaternary amine at one end and to the amine of the polymer backbone at the other end. These examples are considered appropriate comparisons of the differences between the resulting efficacy of free, or terminal, hydrophobic groups, and those that are internal to the alkylating agent, between the quaternary amine and the amine polymer. Compared to Example 19 (an example of the hydrophobe between the quaternary amine and the amine polymer), these examples were selected to have the same total number of carbon atoms (Example 12), or the same length of individual hydrophobe ( Example 13), or the same number of carbons in an unbranched segment (11; Example 10). Furthermore, based on the yields of the alkylation reactions, these polymers all have a similar number of alkylating agents attached to the polymer backbone. The sequestrants obtained in Examples 10, 12, 13 and 19 were tested in vivo in hamsters. Animals were injected peritoneally with a solution of bile acids labeled with 14C (Colic and chenodeoxycholic acids). Bile acids marked are presented in the same relationship (3: 1, colic: chenodeoxycholic) that the one that exists in the bile of the gallbladder. They enter the gallbladder and are incorporated into the endogenous background of the animal. The animals are then fed a diet containing drug, for 36 hours, collecting feces for the last 29 hours. Fecal samples are treated and their radioactivity determined. The results are expressed as percentages or radiotracer excreted on the control animals that have not been fed with sequestrant.

Example Activity * 10 184% 12 200% 13 184% 19 143% * Radioactivity excreted per gram of faeces compared to control without sequestrant From these data it follows that for sequestrants with equivalent "hydrophobic" chain lengths, the terminal hydrophobic alkyl groups result in sequestrants significantly more potent than those in which the hydrophobic alkyl group it is internal.

Equivalents Those skilled in the art will understand, or may prove with simple routine experimentation, many equivalents to the specific embodiments of the invention specifically described herein. These equivalents are considered included in the framework of the following claims.

Claims

CLAIMS 1. A crosslinked poly (allylamine) polymer, comprising a substituent attached to an amine of said polymer, the substituent including a quaternary amine containing radical, wherein the nitrogen of the quaternary amine of said radical is attached to the amine of the polymer by an alkylene having three or more carbons 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 carbons and the remaining terminal substituents are, each independently, a group alkyl having between 1 and about 5 carbons.
2. The crosslinked poly (allylamine) polymer of claim 1, wherein said alkylene has 3 carbons, the hydrophobic alkyl group is an octyl group and the remaining terminal substituents are methyl groups.
3. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 3 carbons, the hydrophobic alkyl group is a decyl group and the remaining terminal substituents are methyl groups.
4. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 3 carbons, the Hydrophobic alkyl group is a dodecyl group and the remaining terminal substituents are methyl groups.
5. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 4 carbons, the hydrophobic alkyl group is an octyl group and the remaining terminal substituents are methyl groups.
6. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 4 carbons, the hydrophobic alkyl group is a decyl group and the remaining terminal substituents are methyl groups.
7. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 4 carbons, the hydrophobic alkyl group is a dodecyl group and the remaining terminal substituents are methyl groups.
8. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 5 carbons, the hydrophobic alkyl group is an octyl group and the remaining terminal substituents are methyl groups.
9. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 5 carbons, the hydrophobic alkyl group is a decyl group and the remaining terminal substituents are methyl groups.
10. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 5 carbons, the hydrophobic alkyl group is a dodecyl group and the remaining terminal substituents are methyl groups.
11. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 6 carbons, the hydrophobic alkyl group is an octyl group and the remaining terminal substituents are methyl groups.
12. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 6 carbons, the hydrophobic alkyl group is a decyl group and the remaining terminal substituents are methyl groups.
13. The crosslinked poly (allylamine) polymer according to claim 1, wherein said alkylene has 6 carbons, the hydrophobic alkyl group is a dodecyl group and the remaining terminal substituents are methyl groups.
14. A crosslinked poly (allylamine) polymer obtained by a method comprising the step of reacting a crosslinked poly (allylamine) with a quaternary amine containing compound having the formula R X (CH2) n - N + R R wherein, R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining have, each independently, from 1 to about 5 carbons, n is an integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter-ion.
15. The crosslinked poly (allylamine) polymer according to claim 14, wherein n is from 3 to about 6.
16. The crosslinked poly (allylamine) polymer according to claim 15, wherein n is 3, at least one alkyl is an octyl group and the remaining alkyl groups are methyl groups.
17. The crosslinked poly (allylamine) polymer according to claim 15, wherein n is 3, at least one alkyl is a decyl group and the remaining alkyl groups are methyl groups.
18. The crosslinked poly (allylamine) polymer according to claim 15, wherein n is 3, at least one alkyl group is a dodecyl group and the remaining alkyl groups are methyl groups.
19. The crosslinked poly (allylamine) polymer according to 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 according to 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 according to claim 15, wherein n is 4, at least one alkyl group is a dodecyl group and the remaining alkyl groups are methyl groups.
22. The crosslinked poly (allylamine) polymer according to 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 according to 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 according to claim 15, wherein n is 5, at least one alkyl group is a dodecyl group and the remaining alkyl groups are methyl groups.
25. The crosslinked poly (allylamine) polymer according to 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 according to claim 15, wherein n is 6, at least one alkyl is a decyl group and the remaining alkyl groups are methyl groups.
27. The crosslinked poly (allylamine) polymer according to claim 15, wherein n is 6, at least one alkyl group is a dodecyl group and the remaining alkyl groups are methyl groups.
28. A hydrocarbon amine polymer, comprising a substituent attached to an amine of said polymer, the substituent including a quaternary amine containing radical, wherein the nitrogen of the quaternary amine of said radical is attached to the amine of the polymer by an alkylene having 3 or more carbons and wherein at least 2 of the 3 substituents of the quaternary amine are each a hydrophobic alkyl group having from 6 to about 24 carbons and the other terminal substituent is an alkyl group having from 1 to approximately 5 carbons.
29. The hydrocarbon amine polymer according to claim 28, wherein the polymer is crosslinked.
30. A hydrocarbon amine polymer, comprising a substituent attached to an amine of said polymer, the substituent including a quaternary amine containing radical, wherein the nitrogen of the quaternary amine of said radical is attached to the amine of the polymer by an alkylene having three or more carbons and wherein the three terminal substituents of the quaternary amine are hydrophobic alkyl groups having from 6 to about 24 carbons.
31. The hydrocarbon amine polymer according to claim 30, wherein the polymer is crosslinked.
32. A crosslinked hydrocarbon amine polymer obtained by a method comprising the step of reacting a crosslinked amine hydrocarbon polymer with a quaternary amine containing compound having the formula: R I X - (CH2) n - N + - R R wherein, R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining have, each independently, from 1 to about 5 carbons, n is an integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter-ion.
33. The crosslinked hydrocarbon amine hydrocarbon polymer according to claim 32 wherein the polymer is a poly (vinylamine) polymer.
34. The cross-linked hydrocarbon amine polymer according to claim 32 wherein the polymer is a poly (allylamine) polymer.
35. The crosslinked hydrocarbon amine hydrocarbon polymer according to claim 32 wherein the polymer is a poly (ethylene imine) polymer.
36. A method of binding bile salts in a mammal, comprising the step of orally administering to the mammal a therapeutic amount of a crosslinked poly (allylamine) polymer having a substituent attached to an amine of said polymer, the substituent including a radical containing quaternary amine, wherein the nitrogen of the quaternary amine of said radical is bound to the polymer amine by an alkylene having three or more carbons and wherein at least 1 of the 3 terminal substituents of the quaternary amine is a hydrophobic alkyl group which has from 6 to about 24 carbons and the terminal substituents remaining are, each independently, an alkyl group having from 1 to about 5 carbons.
37. A method of binding bile salts in a mammal, comprising the step of orally administering to the mammal a therapeutic amount of a hydrocarbon amine polymer having a substituent attached to an amine of said polymer, the substituent including a radical containing quaternary amine, wherein the nitrogen of the quaternary amine of said radical is attached to the polymer amine by an alkylene having three or more carbons and wherein at least 2 of the three terminal substituents of the quaternary amine are hydrophobic alkyl groups having 6 to about 24 carbons and the remaining terminal substituent is an alkyl group having from 1 to about 5 carbons.
38. A method for reducing blood cholesterol in a mammal, comprising the step of orally administering to the mammal a therapeutic amount of a crosslinked poly (allylamine) polymer having a substituent attached to an amine of said polymer, the substituent including a radical which contains quaternary amine, wherein the nitrogen of the quaternary amine of said radical is attached to the polymer amine by an alkylene having three or more carbons and where at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having from 6 to about 24 carbons and the remaining terminal substituents are, each independently, an alkyl group having from 1 to about 5 carbons.
39. A method for treating atherosclerosis in a mammal, comprising the step of orally administering to the mammal a therapeutic amount of a crosslinked poly (allylamine) polymer having a substituent attached to an amine of said polymer, the substituent including a radical containing quaternary amine, wherein the nitrogen of the quaternary amine of said radical is attached to the polymer amine by an alkylene having three or more carbons 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 carbons and the remaining terminal substituents are, each independently, an alkyl group having from 1 to about 5 carbons.
40. A method for treating hypercholesterolemia in a mammal, comprising the step of orally administering to the mammal a therapeutic amount of a crosslinked poly (allylamine) polymer having a substituent attached to an amine of the said polymer, the substituent including a quaternary amine containing radical, wherein the nitrogen of the quaternary amine of said radical is attached to the polymer amine by an alkylene having three or more carbons and wherein at least 1 of the 3 terminal substituents of the quaternary amine is a hydrophobic alkyl group having from 6 to about 24 carbons and the remaining terminal substituents are, each independently, an alkyl group having from 1 to about 5 carbons.
41. A method for reducing the plasma lipid content of a mammal, comprising the step of orally administering to the mammal a therapeutic amount of a cross-linked poly (allylamine) polymer having a substituent attached to an amine of said polymer, including the substituent a quaternary amine containing radical, wherein the nitrogen of the quaternary amine of said radical is attached to the polymer amine by an alkylene having three or more carbons 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 carbons and the remaining terminal substituents are, each independently, an alkyl group having from 1 to about 5 carbons.
42. A quaternary ammonium compound, comprising: R X - (CH2) n - N + -R R wherein, R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the remaining have, each independently, from 1 to about 5 carbons, n is an integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter-ion.
43. The compound according to claim 42, wherein 1 or 2 of said alkyl groups is a methyl group.
44. The compound according to claim 43 wherein n is from 3 to about 8.
45. The compound according to claim 44 wherein X is a halide.
46. A quaternary ammonium compound, comprising: R X - (CH2) n - N + -R wherein, R represents an alkyl group, at least one of which has from 6 to about 24 carbons and the rest of them has, each independently, 1 to 5 carbons, n is an integer having a value of 3 or more, X is a leaving group, and Y is a negatively charged counter-ion.
47. The compound according to claim 46, wherein an alkyl group is a methyl group.
48. The compound according to claim 47, wherein n has a value from 3 to about 8.
49. The compound of claim 48, wherein X is a halide.
50. A quaternary ammonium compound, comprising: R X (CH2) n - N + -R R wherein, R represents an alkyl group, having from 6 to about 24 carbons; n is an integer that has a value of 3 or more, X is a leaving group, and Y is a negatively charged counter-ion.
51. The compound according to claim 50, wherein n is between 3 and about 8.
52. The compound according to claim 51, wherein X is a halide.
53. A method of preparing a quaternary ammonium compound having the formula R X - (CH2) n - N + -R R comprising the reaction stage of a tertiary amine having the formula R N - R R wherein, R represents an alkyl group, at least one of which has 6 to about 24 carbons, and the rest of which independently has 1 to about 5 carbons, with an asymmetric dihalide that has the formula X1 - (CH2) n - X2 where X1 is chloride, X2 is bromide, and n is an integer with a value of 3 or more.
54. A method of preparing a quaternary ammonium compound having the formula R X - (CH2) n - N + -R I Y- R comprising the reaction step of a tertiary amine having the formula R I N - R R wherein, R represents an alkyl group, at least two of which have from 6 to about 24 carbons, and the remaining has independently from 1 to 5 carbons, with an asymmetric dihalide having the formula X1 - (CH2) n - X2 where X1 is chloride, X2 is bromide, and n is an integer with a value of 3 or more.
55. A method of preparing a quaternary ammonium compound having the formula R X - (CH2) n - N + -R R comprising the reaction stage of a tertiary amine having the formula R I N - R I R wherein, R represents an alkyl group, the three having from 6 to about 24 carbons with an asymmetric dihalide having the formula X1 - (CH2) n -X < where X1 is chloride, X2 is bromide, and n is an integer with a value of 3 or more.
56. A poly (allylamine) polymer, comprising a substituent attached to an amine of said polymer, the substituent including a quaternary amine radical, wherein the quaternary amine nitrogen of said radical is attached to the amine of the polymer by an alkylene having three or more carbons 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 carbons and the remainder terminal substituents are, each independently, an alkyl group having from 1 to about 5 carbons.
57. The poly (allylamine) polymer according to claim 56 wherein said alkylene has three carbons, the hydrophobic alkyl group is an octyl group and the remaining terminal substituents are methyl groups.
58. The poly (allylamine) polymer according to claim 56, wherein said alkylene has three carbons, the hydrophobic alkyl group is a decyl group and the remaining terminal substituents are methyl groups.
59. The poly (allylamine) polymer according to claim 56, wherein said alkylene has three carbons, the hydrophobic alkyl group is a dodecyl group and the remaining terminal substituents are methyl groups.
60. The poly (allylamine) polymer according to claim 56, wherein said alkylene has four carbons, the hydrophobic alkyl group is an octyl group and the remaining terminal substituents are methyl groups.
61. The poly (allylamine) polymer according to claim 56, wherein said alkylene has four carbons, the hydrophobic alkyl group is a decyl group and the remaining terminal substituents are methyl groups.
62. The poly (allylamine) polymer according to claim 56, wherein said alkylene has four carbons, the hydrophobic alkyl group is a dodecyl group and the remaining terminal substituents are methyl groups.
63. The poly (allylamine) polymer according to claim 56, wherein said alkylene has 5 carbons, the hydrophobic alkyl group is an octyl group and the remaining terminal substituents are methyl groups.
64. The poly (allylamine) polymer according to claim 56, wherein said alkylene has 5 carbons, the hydrophobic alkyl group is a decyl group and the remaining terminal substituents are methyl groups.
65. The poly (allylamine) polymer according to claim 56, wherein said alkylene has 5 carbons, the hydrophobic alkyl group is a dodecyl group and the remaining terminal substituents are methyl groups.
66. The poly (allylamine) polymer according to claim 56, wherein said alkylene has 6 carbons, the hydrophobic alkyl group is an octyl group and the remaining terminal substituents are methyl groups.
67. The poly (allylamine) polymer according to claim 56, wherein said alkylene has 6 carbons, the hydrophobic alkyl group is a decyl group and the remaining terminal substituents are methyl groups.
68. The poly (allylamine) polymer according to claim 56, wherein said alkylene has 6 carbons, the hydrophobic alkyl group is a dodecyl group and the remaining terminal substituents are methyl groups.