CN101541235A

CN101541235A - Amine dendrimers

Info

Publication number: CN101541235A
Application number: CNA200780034540XA
Authority: CN
Inventors: S·雷多·霍尔姆斯-法利; 普拉迪普·K·戴尔; 查德·C·胡瓦尔
Original assignee: Genzyme Corp
Current assignee: Genzyme Corp
Priority date: 2006-07-18
Filing date: 2007-07-16
Publication date: 2009-09-23

Abstract

Ion binding compounds and compositions may include compounds, polymers and compositions that include amine moieties. Ion binding polymers may be crosslinked amine polymers and may be used to remove ions, such as phosphate ions, from the gastrointestinal tract of animals, such as humans. Such compounds, polymers and compositions may be used therapeutically to treat a variety of medical conditions, such as hyperphosphatemia.

Description

Amine dendrimers

Technical field

The present invention relates to the ionic polymeric material of combining target, more specifically, the present invention relates to the pharmaceutically acceptable ionic aminated compounds of combining target, polymer and the compositions of being used for.

Background technology

Hyperphosphatemia is often followed the disease relevant with renal insufficiency such as End Stage Renal Disease (ESRD), hyperparathyroidism and other symptom that some is concrete.These symptoms if particularly there is the long time, will cause the severely subnormal of alcium and phosphor metabolization, and show abnormal calcification in joint, lung and eyes.

The treatment that reduces serum paraoxonase comprises dialysis, reduce the absorption with the reduction the intestines and stomach of phosphorus in the diet and oral insoluble phosphorus bonding agent.Many these class treatments have multiple unfavorable side effect and/or the phosphorus binding ability is not best, comprise effect and curative effect.The compositions and the treatment that therefore, need have good phosphorus binding ability and few side effects.

Summary of the invention

On the one hand, the present invention relates to contain chemical compound, polymer and the compositions of crosslinked amine moiety.Described polymer can be crosslinked amine polymer.Described compositions can contain one or more crosslinked amine polymers.Below the several embodiments of the present invention that comprise this respect are further specified.Usually, unless stated otherwise, each in these embodiments all can be used with different concrete combinations, and can be used in combination with others and embodiment.

Except chemical compound and polymer that the present invention puts down in writing herein, other form of chemical compound and polymer is also included within the scope of the present invention, and it comprises chemical compound and/or polymer pharmaceutically acceptable salt, solvate, hydrate, prodrug, polymorphic, clathrate, isotopic variations and its mixture.

In addition, chemical compound of the present invention and polymer can have optical center, chiral centre or two key, and aminated compounds of the present invention and amine polymer comprise all isomeric forms of these chemical compounds and polymer, comprise optically pure form, racemic modification, diastereomer, enantiomer, tautomer and/or its mixture.

In the first embodiment, the present invention is crosslinked amine polymer, is made up of crosslinked amine polymer substantially, or comprises crosslinked amine polymer, and wherein said amine polymer comprises or is derived from the aminated compounds shown in the formula I or its residue, and is as follows:

Formula I

Wherein:

R represents independently:

R ₁Expression independently:

R ₂Expression independently:

R _AExpression independently:

Wherein, m represents 1 to 20 integer independently, and for example, 1-15,1-2,3-6,7-10,11-15 are such as 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20; N and s represent 1 to 20 integer independently, and for example, 1-15,1-2,3-5,6-10,11-15 are such as 2,3,4,5 or 6; Q and r represent the integer of 0-2 independently, as 0,1 or 2; And R ' represents hydrogen or replacement or unsubstituted alkyl or replacement or unsubstituted aryl independently; Or R ' and contiguous R ' represent to comprise one or more connection the (described cross-linking agent is for example epoxychloropropane or other cross-linking agent), replacement or unsubstituted alicyclic group, replacement or unsubstituted aromatic group or the replacement or the unsubstituted heterocyclic group of the residue of cross-linking agent together; Or being connected of R ' expression and another chemical compound, as another aminated compounds or its residue, another polymer or its residue or crosslinker compound or its residue.

On the other hand, the invention provides the method that the treatment animal comprises the people.This method generally includes the of the present invention crosslinked amine polymer of using effective dose.

On the other hand, the present invention relates to pharmaceutical composition, described pharmaceutical composition contains one or more polymer of the present invention, and at least a pharmaceutically acceptable carrier.Polymer of the present invention has many treatments and uses.For example, described crosslinked amine polymer can be used in deionizing from intestines and stomach, as phosphate radical.In some embodiments, described crosslinked amine polymer is used for the treatment of unbalance disorder of phosphate and nephropathy.

On the other hand, described crosslinked amine polymer is used to remove other anion solute, as chloride, heavy carbonate and/or oxalate ion.The polymer of removing oxalate ion is found and can be used for treating the unbalance disorder of oxalates.For example, the polymer of removing chloride ion is found and can be used for treating acidity disease.In some embodiments, described crosslinked amine polymer is used to remove bile acid and relevant chemical compound.

The present invention further provides the compositions that contains any above-mentioned polymer, wherein said polymer is a particle form, and described polymer beads is packaged in the outer shell.

On the other hand, the invention provides pharmaceutical composition.In one embodiment, described pharmaceutical composition contains crosslinked aminated compounds of the present invention and pharmaceutically acceptable excipient.In some embodiments, described compositions is a liquid preparation, and wherein said polymer dispersed is in the liquid medium of water and appropriate excipients.In some embodiments, pharmaceutical composition provided by the invention contains and is useful on the ionic polymer of combining target and one or more suitable drug excipients, and the form of wherein said compositions is tablet, XIANGFEN, slurry, food formulation, tablet, capsule, elixir, suspension, syrup, disk, chewing gum or lozenge.In some embodiments, described compositions contains the drug excipient that is selected from sucrose, mannitol, xylitol, maltodextrin, fructose, sorbitol and its combination.In some embodiments, the target anion of described polymer is a phosphate radical.In some embodiments, described polymer surpasses 50% of tablet weight approximately.In some embodiments, described tablet is that diameter is about 12mm to about 28mm, highly is about 1mm about 8mm cylindric extremely, and described polymer contains and accounts for the tablet total weight amount above 0.6gm about 2.0gm extremely.In some compositions of the present invention, described excipient is selected from sweeting agent, binding agent, lubricant and disintegrating agent.Selectable, the average diameter of described polymer beads is less than about 80 μ m.In some embodiments, described sweeting agent is selected from sucrose, mannitol, xylitol, maltodextrin, fructose, sorbitol and its combination.

The specific embodiment

Amine polymer

On the one hand, the invention provides these chemical compounds of chemical compound, compositions and use and method for compositions, wherein these chemical compounds and compositions contain the aminated compounds that comprises formula I or the polymer of its residue.In some embodiments, described aminated compounds can be crosslinked.In some embodiments, it can be the polymer of homopolymer or copolymer that chemical compound comprises, and wherein said homopolymer or copolymer comprise, for example, copolymer comprises or is derived from two or more aminated compoundss of the present invention.

In addition, can be included in multiple a plurality of aminated compoundss in copolymer or the polymer in some embodiments.These polymer can comprise one or more other chemical compounds, and described other chemical compounds can be included in the main polymer chain, and perhaps as separately or the side group of recurring group, and it can provide separation between independent aminated compounds.

Unless stated otherwise, term used herein " is derived from " and is interpreted as: produce from another kind of material or obtain by chemical reaction, particularly directly obtain from reactant, for example, the aminated compounds that reacts with cross-linking agent generates the polymer that is derived from this aminated compounds.

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula I or its residue, and is as follows:

Formula I

Wherein:

R represents independently:

R ₁Expression independently:

R ₂Expression independently:

R _AExpression independently:

Wherein, m represents 1 to 20 integer independently, and for example, 1-15,1-2,3-6,7-10,11-15 are such as 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20; N and s represent 1 to 20 integer independently, and for example, 1-15,1-2,3-5,6-10,11-15 are such as 2,3,4,5 or 6; Q and r represent the integer of 0-2 independently, as 0,1 or 2; And R ' represents hydrogen or replacement or unsubstituted alkyl or replacement or unsubstituted aryl independently; Or R ' and contiguous R ' represent to comprise one or more connection the (described cross-linking agent is for example epoxychloropropane or other cross-linking agent), replacement or unsubstituted alicyclic group, replacement or unsubstituted aromatic group or the replacement or the unsubstituted heterocyclic group of cross-linking agent residue together; Or being connected of R ' expression and another chemical compound.

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula II or its residue, and is as follows:

Formula II

Wherein:

R represents independently:

R ₁Expression independently:

R ₂Expression independently:

R ₃Expression independently:

R ₄Expression independently:

Wherein, m represents 1 to 20 integer independently, and for example, 1-15,1-2,3-6,7-10,11-15 are such as 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20; N, s, t and v represent 1 to 20 integer independently, and for example, 1-15,1-2,3-5,6-10,11-15 are such as 2,3,4,5 or 6; And R ' represents hydrogen or replacement or unsubstituted alkyl or replacement or unsubstituted aryl independently; Or R ' and contiguous R ' represent to comprise one or more connection the (described cross-linking agent is for example epoxychloropropane or other cross-linking agent), replacement or unsubstituted alicyclic group, replacement or unsubstituted aromatic group or the replacement or the unsubstituted heterocyclic group of the residue of cross-linking agent together; Or being connected of R ' expression and another chemical compound.

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula III or its residue, and is as follows:

Formula III

Wherein:

R represents independently:

R ₁Expression independently:

R ₂Expression independently:

R ₃Expression independently:

R ₄Expression independently:

R ₅Expression independently:

Wherein, m represents 1 to 20 integer independently, and for example, 1-15,1-2,3-6,7-10,11-15 are such as 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20; N, s, t, v and w represent 1 to 20 integer independently, and for example, 1-15,1-2,3-5,6-10,11-15 are such as 2,3,4,5 or 6; And R ' represents hydrogen or replacement or unsubstituted alkyl or replacement or unsubstituted aryl independently; Or R ' and contiguous R ' represent to comprise one or more connection the (described cross-linking agent is for example epoxychloropropane or other cross-linking agent), replacement or unsubstituted alicyclic group, replacement or unsubstituted aromatic group or the replacement or the unsubstituted heterocyclic group of the residue of cross-linking agent together; Or being connected of R ' expression and another chemical compound.

In some embodiments, described aminated compounds or its residue can be shown in following formula IV:

Formula IV

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula V or its residue, and is as follows:

Formula V

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula VI or its residue, and is as follows:

Formula VI

Wherein:

R ₆Expression independently:

Wherein, p, q and r represent the integer of 0-2 independently, as 0,1 or 2; And R ' represents hydrogen or replacement or unsubstituted alkyl independently; Or R ' and contiguous R ' represent to comprise one or more connection the (described cross-linking agent for example be epoxychloropropane or other cross-linking agent) of the residue of cross-linking agent together; Or being connected of R ' expression and another chemical compound.

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula VII or its residue, and is as follows:

Formula VII

Wherein:

R represents independently:

R ₆Expression independently:

Wherein, m represents 1 to 8 integer independently, and for example, 1-2,2-6,6-8 are such as 1,2,3,4,5,6,7 or 8; P, q and r represent the integer of 0-2 independently, as 0,1 or 2; And R ' represents hydrogen or replacement or unsubstituted alkyl independently; Or R ' and contiguous R ' represent to comprise one or more connection the (described cross-linking agent for example be epoxychloropropane or other cross-linking agent) of the residue of cross-linking agent together; Or being connected of R ' expression and another chemical compound.

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula VIII or its residue, and is as follows:

Formula VIII

Wherein

R ₆Expression independently:

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula IX or its residue, and is as follows:

Formula IX

Wherein:

R ₇Expression independently:

R ₁Expression independently:

Wherein, n represents 1 to 6 integer independently, and for example, 2-6,1-2 or 3-5 are such as 1,2,3,4,5 or 6; P, q and r represent the integer of 0-2 independently, as 0,1 or 2; And R ' represents hydrogen or replacement or unsubstituted alkyl independently; Or or R ' and contiguous R ' represent to comprise one or more connection (described cross-linking agent for example be epoxychloropropane or other cross-linking agent) of the residue of cross-linking agent together; Or being connected of R ' expression and another chemical compound.

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula X or its residue, and is as follows:

Formula X

Wherein:

R ₇Expression independently:

R represents independently:

R ₁Expression independently:

Wherein, m represents 1 to 8 integer independently, and for example, 1-2,2-6,6-8 are such as 1,2,3,4,5,6,7 or 8; N represents 1 to 6 integer independently, and for example, 2-6,1-2 or 3-5 are such as 1,2,3,4,5 or 6; P, q and r represent the integer of 0-2 independently, as 0,1 or 2; And R ' represents hydrogen or replacement or unsubstituted alkyl independently; Or R ' and contiguous R ' represent to comprise one or more connection the (described cross-linking agent for example be epoxychloropropane or other cross-linking agent) of the residue of cross-linking agent together; Or being connected of R ' expression and another chemical compound.

In some embodiments, the present invention relates to chemical compound or compositions, or from the animal intestines and stomach, remove phosphatic method by the polymer of using effective dose, wherein said polymer comprises or is derived from the aminated compounds shown in the formula XI or its residue, and is as follows:

Formula XI

Wherein:

R ₇Expression independently:

R ₁Expression independently:

Wherein, n represents 1 to 6 integer independently, and for example, 2-6,1-2 or 3-5 are such as 1,2,3,4,5 or 6; P, q and r represent the integer of 0-2 independently, as 0,1 or 2; And R ' represents hydrogen or replacement or unsubstituted alkyl independently; Or R ' and contiguous R ' represent to comprise one or more connection the (described cross-linking agent for example be epoxychloropropane or other cross-linking agent) of the residue of cross-linking agent together; Or being connected of R ' expression and another chemical compound.

In one embodiment, described aminated compounds can be shown in following formula XII or its residue:

Formula XII

In some embodiments, the example of suitable aminated compounds can be: 4,25-two (3-aminopropyl)-12,17-[3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group]-8,21-two [3-[two (3-aminopropyl) amino] propyl group]-4,8,12,17,21,25-six azepine octacosanes-1, the 28-diamidogen; 1,4-two [two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] butane; 4,33-two (3-aminopropyl)-8,29-two [3-[two (3-aminopropyl) amino] propyl group]-12,25-two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group]-16,21-two [3-[two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] propyl group]-4,8,12,16,21,25,29,33-eight azepine hexatriacontanes-1, the 36-diamidogen; 1,4-two [two [3-[two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] propyl group] amino] butane; Or 1,4-two [two [3-[two [3-[two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] propyl group] amino] propyl group] amino] butane.

In one embodiment, the example of suitable aminated compounds can be N, N, N ', N '-four (3-aminopropyl)-1,3-propane diamine.In another embodiment, suitable aminated compounds can be to have 1, and the aminoethyl ethanolamine tree of 4-diamidogen butane nuclear comprises tree 1-6 generation.

In some embodiments, described aminated compounds is for surpassing a kind of mixture of aminated compounds, and for example 2-20 (as 2,3,4,5,6,7,8,9 or 10) plants by the aminated compounds shown in the formula I-XII.In some embodiments, described mixture mainly contains the aminated compounds shown in a kind of among the formula I-XII, and wherein p, q and r are 0 or 2 independently.For example, in some embodiments, mixture main (for example accounting for mixture total weight greater than 30wt.%, greater than 40wt.%, greater than 50wt.%, greater than 60wt.% or greater than 70wt.%) comprises aminated compounds or its residue shown in a kind of among the formula I-XII, and wherein p, q and r are 0 or 2 independently.For example, in some embodiments, described mixture comprises greater than 30wt.%, greater than 40wt.%, greater than 50wt.%, greater than 60wt.% or greater than formula IV or the aminated compounds shown in the formula V or its residue of 70wt.%.

In some embodiments, the present invention includes the polymer (described polymer is the mixture of aminated compounds) that is derived from aminated compounds, the pharmaceutical composition that contains described polymer or use the same polymer of treatment effective dose from the animal intestines and stomach, to remove the method for chemical compound or ion (as phosphorus-containing compound or contain phosphonium ion (as phosphate)).

Other embodiment of the present invention is included in the polymer that has the side group that aminated compounds or its residue form on the polymer main chain of polymer or polymer.This polymer can form like this: one or more polymerizable groups are added on one or more amino on the aminated compounds to form the amine monomer, contain the polymer of aminated compounds or its residue with these polymerizable groups of post polymerization with formation.The illustrative example of this addition [should note: what be called hereinafter that the aminated compounds of " AC " is used for representing is aminated compounds of the present invention or its residue, and shows amino to illustrate polymerisable group is how to join in the aminated compounds] as follows:

According to embodiment of the present invention, the limiting examples of other polymerizable groups that can use with aminated compounds or its residue comprises:

One or more polymerizable groups can be added in each aminated compounds, thereby might obtain the monomeric mixture of amine, and described amine monomer has different side group AC, and described side group AC has the polymerizable groups of different numbers.In addition, the polymer of preparation can be after polymerization carries out modification, crosslinked, formation net or replacement with technology known to a person of ordinary skill in the art by this way.Can comprise and improve effect, toleration or reduce side effect because of a plurality of former thereby carry out these modifications.

By the reaction of the one or more amine reactive groups on monomeric one or more amino of amine and the amine reactive polymer, also can form the amine monomer by adding aminated compounds to the amine reactive polymer.The example of some amine reactive polymers comprises:

Aminated compounds or amine monomer also can be used as multi-functional amine monomer and form polymer.For example, when the aminated compounds that is formed by the amine monomer or polymer are crosslinked, described cross-linking reaction can be carried out in bulk solution (promptly using pure amine and pure cross-linking agent) or disperse medium.When using bulk process, thus selective reagent its can be total to molten reactant, and do not disturb cross-linking reaction.Suitable solvent comprises water, low-boiling point alcohol (methanol, ethanol, butanols), dimethyl formamide, dimethyl sulfoxine, acetone, methyl ethyl ketone and analog.

Other polymerization can comprise single polyreaction, pass through each monomeric progressively addition of serial reaction, the progressively addition of monomer block, above-mentioned combination, perhaps any other method of polyreaction, for example directly or anti-phase suspension, concentrate, the polymerization in the emulsifying, sedimentation, aerosol or use polymerisation in bulk/cross-linking method, and the method that reduces size, as extruding and grinding.These methods can carry out in batches, semicontinuously carry out and carry out continuously.For the technology in the disperse medium, described continuous phase can be selected from non-polar solven, as toluene, benzene, hydro carbons, halogenated solvent, critical carbon dioxide and analog.For direct suspension process, can make water, although saline also can be used for the amine and the cross-linking agent of " saltouing " droplet separation in mutually.

Polymer of the present invention can with one or more other monomers or oligomer or other polymerizable groups copolymerization, can be crosslinked, cross-linking agent or other bridging agent can be arranged in main polymer chain or connect monomer, or have as the cross-linking agent of side group or other bridging agent or connect monomer, perhaps can form or polymerization forms the net of aminated compounds or its residue, amine monomer or its residue, or form the blended net of aminated compounds or its residue, amine monomer or its residue.Described net can comprise identical or different intermolecular a plurality of connections, and described connection can be directly, maybe can comprise one or more linking groups, as cross-linking agent or other monomer or oligomer or its residue.

The limiting examples of the comonomer that can be used alone or in combination comprises: styrene, the styrene that replaces, alkyl acrylate, the alkyl acrylate that replaces, the alkyl acrylic methyl ester, the alkyl acrylic methyl ester that replaces, acrylonitrile, methacrylonitrile, acrylamide, Methacrylamide, the N-alkyl acrylamide, N-alkyl methyl acrylamide, N, N-dialkyl group acrylamide, N, N-dialkyl methyl acrylamide, isoprene, butadiene, ethylene, ethyl acetate, the N-vinylamide, maleic acid derivatives, vinyl ethers, allyle, methacrylic monomer and combination thereof.These monomeric functionality variants also can use.Other the concrete monomer or the comonomer that can use in the present invention include but not limited to methyl methacrylate, the ethylacrylic acid methyl ester, the propyl group acrylic acid methyl ester., butylacrylic acid methyl ester (all isomers), 2-ethylhexyl acrylic acid methyl ester. (all isomers), the isobornyl acrylic acid methyl ester., methacrylate, the benzyl acrylic acid methyl ester., the phenylacrylic acid methyl ester, methacrylonitrile, α-Jia Jibenyixi, methacrylate, the ethyl propylene acid esters, propyl group acrylate (all isomers), butylacrylic acid ester (all isomers), the 2-ethylhexyl acrylate, iso-bornyl acrylate, acrylic acid, the benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, the (+)-2,3-Epoxy-1-propanol acrylic acid methyl ester., 2-hydroxyethyl acrylic acid methyl ester., hydroxypropyl acrylic acid methyl ester. (all isomers), hydroxybutyl acrylic acid methyl ester. (all isomers), N, N-dimethylaminoethyl acrylic acid methyl ester., N, N dimethylamine base ethylacrylic acid methyl ester, the 2,2'-ethylenedioxybis(ethanol). acrylic acid methyl ester., itaconic anhydride, the itaconic acid, epihydric alcohol acrylic ester, the 2-hydroxy ethyl methacrylate, hydroxypropyl acrylate (all isomers), hydroxyl butylacrylic acid ester (all isomers), N, N-dimethylaminoethyl acrylate, N, N-diethylamino ethyl propylene acid esters, the triethyl group EDIA, Methacrylamide, N methacrylamide, N, the N-DMAA, N-tert-butyl group Methacrylamide, N, N-butyl methyl acrylamide, N-methanol Methacrylamide, N-ethanol Methacrylamide, N tert butyl acrylamide, N-n-butyl acrylamide, N hydroxymethyl acrylamide, N-ethoxy acrylamide, the 4-aryl morpholine, vinyl benzoic acid (all isomers), diethylamino acid styrene (all isomers), α-methylvinyl benzoic acid (all isomers), lignocaine α-Jia Jibenyixi (all isomers), p-styryl sulfonic acid, p-styrene sulfonic acid base sodium salt, the triethoxysilylpropyl acrylic acid methyl ester., three butoxy silicon propyl group acrylic acid methyl ester .s, dimethoxy silicon propyl group acrylic acid methyl ester., diethoxy silicon propyl group acrylic acid methyl ester., dibutoxy silicon propyl group acrylic acid methyl ester., diisopropoxy silicon propyl group acrylic acid methyl ester., trimethoxy silicon propyl group acrylate, the triethoxysilylpropyl acrylate, three butoxy silicon propyl group acrylate, dimethoxy-methyl silicon propyl group acrylate, diethoxymethyl silicon propyl group acrylate, dibutoxy methyl silicon propyl group acrylate, diisopropoxy methyl silicon propyl group acrylate, dimethoxy silicon propyl group acrylate, diethoxy silicon propyl group acrylate, dibutoxy silicon propyl group acrylate, diisopropoxy silicon propyl group acrylate, maleic anhydride, N-phenylmaleimide, the N-butyl maleimide, the N-methyl styrene, the N-vinyl acetamide, allylamine, the methyl-prop enamine, propenyl, methyl-vinyl ethers, ethyl vinyl ether, butyl vinyl ether, butadiene, isoprene, chlorobutadiene, ethylene, vinyl acetate, and combination.

In some embodiments, polymer of the present invention carries out crosslinked with cross-linking agent, and may be insoluble to solvent, and expands in solvent at the most.Expansion rate is usually being about 1 to about 20, as 2 to 10,2.5 to 8,3 to 6, as less than 5, less than 6 or less than in 7 the scope.In some embodiments, described polymer can comprise cross-linking agent or other bridging agent, and these cross-linking agent or other bridging agent make polymer not form colloid in solvent, and can dissolve or be partly dissolved in some reagent.

Cross-linking agent normally has the chemical compound that has two functional groups at least, and described functional group is selected from halogen group, carbonyl, epoxy radicals, ester group, anhydride, acid halide group, isocyanate groups, vinyl and chloro-carbonic acid ester group.Described cross-linking agent can link to each other with carbon backbone chain, or links to each other with the nitrogen of aminated compounds, amine monomer or its residue.

The example that is suitable for the cross-linking agent of synthetic polymer of the present invention includes but not limited to one or more multifunctional cross-linking agent, as: dihalo alkane, alkylhalide group oxirane, alkyl epoxy ethane sulfonic acid ester, two (alkylhalide group) amine, three (alkylhalide group) amine, diepoxide, triepoxides, the Fourth Ring oxide, two (halomethyl) benzene, three (halomethyl) benzene, four (halomethyl) benzene, epoxychloropropane, epoxychloropropane, epoxy bromopropane gathers (epoxychloropropane), (iodomethyl) oxirane, the glycidyl tosylate, glycidyl 3-nitrobenzene-sulfonic acid ester, 4-sulphonyl oxygen-1, the 2-epoxy butane, bromo-1, the 2-epoxy butane, 1, the 2-Bromofume, 1, the 3-dichloropropane, 1, the 2-dichloroethanes, 1-bromo-2-ethyl chloride, 1, the 3-dibromopropane, two (2-dichloroethyl ether) amine, three (2-dichloroethyl ether) amine, with two (2-dichloroethyl ether) methylamine, 1,3-butadiene diepoxide, 1,5-hexadiene epoxide, diglycidyl ether, 1,2,7,8-diepoxy octane, 1,2,9,10-diepoxy decane, the ethylene glycol diglycidyl ether, the propyleneglycoles diglycidyl ether, 1, the 4-butanediol diglycidyl ether, 1,2 ethylene glycol bisthioglycolate glycidyl ethers, the glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N, N-two glyceryl aniline, the neopentyl glycol diglycidyl ether, the diethylene glycol diglycidyl ether, 1,4-two (glycidyl oxygen) benzene, the resorcinol diglycidyl ether, 1,6-hexanediol diglycidyl ether, the trimethyl propane diglycidyl ether, 1,4-cyclohexanedimethanol diglycidyl ether, 1,3-two-(2, the 3-glycidoxy)-2-(2,3-dihydroxy third oxygen) propane, 1,2-cyclohexane dicarboxylic acid diglycidyl ester, 2,2 '-two (glycidyl oxygen) diphenyl methane, diphenol F diglycidyl ether, 1,4-two (2 ', 3 '-glycidyl) crosses fluoro-n-butane, 2,6-two (oxirane-2-ylmethyl)-1,2,3,5,6,7-hexahydroxy pyrrolo-[3,4-f] iso-indoles-1,3,5, the 7-tetraketone, diphenol A diglycidyl ether, ethyl 5-hydroxyl-6,8-two (oxirane-2-ylmethyl)-4-oxygen-4h-chromene-2-carboxylate, two [4-(2,3-epoxy-propylthio) phenyl]-sulfide, 1,3-two (3-glycidyl oxygen propyl group) tetramethyl disiloxane, 9,9-two [4-(glycidyl oxygen) phenyl] fluorine, three epoxy chlorinated isocyanurates, glycerol triglycidyl group ether, N, N-diglycidyl-4-glycidyl oxygen aniline, isocyanuric acid (S, S, S)-the triglycidyl group ester, isocyanuric acid (R, R, R)-the triglycidyl group ester, the triglycidyl group chlorinated isocyanurates, the trimethylolpropane tris glycidyl ether, glycerol propoxyl group triglycidyl group ether, three hydroxyphenyl methane triglycidyl group ethers, 3,7,14-three [[3-(glycidoxy) propyl group] dimethyl silane oxygen base]-1,3,5,7,9,11,14-seven cyclopenta three ring [7.3.3.15,11] seven siloxanes, 4,4 '-methylene two (N, N-diglycidylaniline), two (halomethyl) benzene, two (halomethyl) biphenyl, with two (halomethyl) naphthalene, toluene di-isocyanate(TDI), acryloyl chloride, acrylic acid methyl ester., the ethylene acrylamide, pyromellitic acid anhydride, succinyl dichloride., dimethyl succinate.When described cross-linking agent was alkyl halide compound, alkali can be used for the acid that forms during the cleaning reaction.Inorganic base or organic base all are suitable.Preferred NaOH.The ratio of alkali and cross-linking agent is preferably about 0.5 to about 2.

In some embodiments, the amount that described cross-linking agent can 0.5 to 25wt.%, as be about 2 to about 15wt.%, about 2 to about 12wt.%, about 3 to about 10wt.% or about 3 to about 6wt.% is as 2,3,4,5, the amount of 6wt.% imports in the polyreaction.The requirement of cross-linking agent depends on the branch degree in the aminated compounds.

In some embodiments, the molecular weight of amine polymer is at least about 1000 usually.For example, molecular weight can be for about 1000 to about 1,000,000, and according to appointment 1000 to about 750,000, about 1000 to about 500,000, about 1000 to about 250,000, about 1000 to about 100,000, as less than 750,000, less than 500,000,250,000 or less than 100,000.

In some embodiments, pharmaceutical composition of the present invention comprises: amine polymer, described amine polymer comprise or are derived from the aminated compounds shown in the formula VII, wherein, R ' represents hydrogen or alkyl independently, and q and r are 0, and p is 2, and m represents the integer of 3-6 independently, as 3,4,5 or 6; And the cross-linking agent of 2-6wt.% or its residue, cross-linking agent as 2wt.%, 3wt.%, 4wt.%, 5wt.% or 6wt.%, wherein said cross-linking agent is epoxychloropropane, poly-(epoxychloropropane), 1,2-Bromofume, three (2-dichloroethyl ether) amine or 1, the 4-butanediol diglycidyl ether.Another pharmaceutical composition embodiment of the present invention comprises amine polymer, described amine polymer comprises or is derived from the aminated compounds shown in the formula VII, wherein, R ' represents hydrogen or alkyl independently, q is 0, and r and p be 2, and m represents the integer of 3-6 independently, as 3,4,5 or 6, and mutually crosslinked with the defined cross-linking agent of this paragraph.Another pharmaceutical composition in the embodiment of the present invention comprises amine polymer, this amine polymer comprises or is derived from the aminated compounds shown in the formula VII, wherein, R ' represents hydrogen or alkyl independently, q, r and p are respectively 2, m represents the integer of 3-6 independently, as 3,4,5 or 6, and crosslinked with the defined cross-linking agent of this paragraph.

Another pharmaceutical composition of the present invention comprises: amine polymer, described amine polymer comprise or are derived from the aminated compounds shown in the formula VII, and wherein, R ' represents hydrogen independently, and p, q and r represent 0 or 2 independently, and m is 3 or 4; And the cross-linking agent of 3-6wt.% or its residue, as the cross-linking agent of 3wt.%, 4wt.%, 5wt.% or 6wt.%, wherein said cross-linking agent is epoxychloropropane or glycol dibromide.

Another pharmaceutical composition of the present invention comprises amine polymer, and described amine polymer comprises or is derived from the aminated compounds shown in the formula IX, wherein, R ' represents hydrogen or alkyl independently, and q and r are 0, and p is 2, m represents the integer of 3-6 independently, as 3,4,5 or 6; And the cross-linking agent of 2-6wt.% or its residue, cross-linking agent as 2wt.%, 3wt.%, 4wt.%, 5wt.% or 6wt.%, wherein said cross-linking agent is epoxychloropropane, poly-(epoxychloropropane), glycol dibromide, three (2-dichloroethyl ether) amine or 1, the 4-butanediol diglycidyl ether.Another pharmaceutical composition embodiment of the present invention comprises amine polymer, described amine polymer comprises or is derived from the aminated compounds shown in the formula IX, wherein, R ' represents hydrogen or alkyl independently, q is 0, and r and p be 2, and m represents the integer of 3-6 independently, as 3,4,5 or 6, and mutually crosslinked with the cross-linking agent of this paragraph aforementioned definitions.Another pharmaceutical composition embodiment of the present invention comprises amine polymer, described amine polymer comprises or is derived from the aminated compounds shown in the formula IX, wherein, R ' represents hydrogen or alkyl independently, q, r and p are respectively 2, m represents the integer of 3-6 independently, as 3,4,5 or 6, and mutually crosslinked with the cross-linking agent of the above-mentioned definition of this paragraph.The preferred embodiment of another pharmaceutical composition of the present invention comprises amine polymer, and this amine polymer comprises or is derived from the aminated compounds shown in the formula IX, and wherein, R ' represents hydrogen independently, and q, r and p represent 0 or 2 independently, and m is 3 or 4; And the cross-linking agent of 3-6wt.% or its residue, as the cross-linking agent of 3wt.%, 4wt.%, 5wt.% or 6wt.%, wherein said cross-linking agent is epoxychloropropane or glycol dibromide.

Another pharmaceutical composition of the present invention comprises amine polymer, and described amine polymer comprises or is derived from the aminated compounds shown in the formula XI, wherein, R ' represents hydrogen or alkyl independently, and q and r are 0, and p is 2, m represents the integer of 3-6 independently, as 3,4,5 or 6; And the cross-linking agent of 2-6wt.% or its residue, cross-linking agent as 2wt.%, 3wt.%, 4wt.%, 5wt.% or 6wt.%, wherein said cross-linking agent is epoxychloropropane, poly-(epoxychloropropane), 1,2-Bromofume, three (2-dichloroethyl ether) amine or 1, the 4-butanediol diglycidyl ether.Another pharmaceutical composition embodiment of the present invention comprises amine polymer, described amine polymer comprises or is derived from the aminated compounds shown in the formula XI, wherein, R ' represents hydrogen or alkyl independently, q is 0, and r and p be 2, and m represents the integer of 3-6 independently, as 3,4,5 or 6, and mutually crosslinked with the cross-linking agent of the above-mentioned definition of this section.Another pharmaceutical composition embodiment of the present invention comprises amine polymer, described amine polymer comprises or is derived from the aminated compounds shown in the formula XI, wherein, R ' represents hydrogen or alkyl independently, q, r and p are respectively 2, m represents the integer of 3-6 independently, as 3,4,5 or 6, and mutually crosslinked with the cross-linking agent of the above-mentioned definition of this section.The preferred embodiment of another pharmaceutical composition of the present invention comprises amine polymer, and this amine polymer comprises or is derived from the aminated compounds shown in the formula XI, and wherein, R ' represents hydrogen, and q, r and p represent 0 or 2 independently, and m is 3 or 4; And the cross-linking agent of 3-6wt.% or its residue, as the cross-linking agent of 3wt.%, 4wt.%, 5wt.% or 6wt.%, wherein said cross-linking agent is epoxychloropropane or glycol dibromide.

Polymer in some embodiments can form with polymerization initiator.Usually operable any initiator comprise cation and.Some examples of operable suitable initiator comprise: peroxide and azo-compound; as azodiisobutyronitrile; AMBN (azodiisovaleronitrile); the dimethyl azo-bis-isobutyrate; 2; 2 '-azo two (isopropyl cyanide); 2; 2 '-azo, two (N; N '-dimethylene 2,2-Dimethylaziridine) dihydrochloride; 2; 2 '-azo two (2-amidine propane) dihydrochloride; 2; 2 '-azo, two (N; N '-dimethylene 2,2-Dimethylaziridine); 1; 1 '-azo two (1-cyclohexane extraction carboxyl nitrile); 4; 4 '-azo two (4-cyanopentanoic acid); 2; 2 '-azo two (isobutyl amine) dihydride; 2; 2 '-azo two (2-methylpropane); 2,2 '-azo two (2-methylbutyronitrile); VAZO 67; cyanopentanoic acid; peroxide trimethylace tonitric ester; the detergent alkylate peroxide; the phenoxy group peroxide; two-t-butyl perhydride; t-butyl peracetic acid; acetyl peroxide; the peroxide diisopropylbenzene (DIPB); the cumenyl hydrogen peroxide; dimethyl two (crossing oxygen-butyl) hexane.

In some embodiments, according to embodiment of the present invention, any nitrogen-atoms on aminated compounds or its residue is all selectively by quaternized, thereby obtains three grades of nitrogen groups of corresponding positively charged, as the ammonium salt group of ammonium salt or replacement.On aminated compounds or its residue any one or a plurality of nitrogen-atoms can be by quaternized, and are not limited to when this quaternized existence or do not need to comprise the terminal amido nitrogen-atoms.In some embodiments, this quaternized formation that can cause extra net, thus cause crosslinked, connection or amino-reactive group to add on the nitrogen-atoms.The ammonium salt group can link to each other with pharmaceutically acceptable counter ion.

In some embodiments, chemical compound of the present invention can with pharmaceutically acceptable counter ion together partly or entirely by quaternized, comprise protonatedly, wherein said counter ion can be organic ion, inorganic ions or its combination.The example of the inorganic ions that some are suitable comprises: halogenide (as chloride, bromide or iodide), carbonate, heavy carbonate, sulfate, disulfate, hydride, nitrate, persulfate and sulphite.The example of suitable organic ion comprises: acetate, Ascorbate, benzoate, citrate, dihydrogen citrate, acid citrate, oxalates, succinate, tartrate, taurocholate, glycocholate and cholate.Preferred ion comprises chloride and carbonate.

In some embodiments, chemical compound of the present invention and polymer can be by by protonated, thereby the ratio of protonated nitrogen-atoms is 1 to 25%, is preferably 3 to 25%, and more preferably 5 to 15%.

In one embodiment, described pharmaceutically acceptable aminated compounds is the polymer of protonated form, and comprises anion, carbonate.In one embodiment, described pharmaceutically acceptable aminated compounds is the polymer of protonated form, and comprises carbonate and the anionic mixture of heavy carbonate.

In some embodiments, chemical compound of the present invention is characterised in that the ability of its coupled ion.Preferably, chemical compound of the present invention is in conjunction with anion, and preferred, these chemical compounds are in conjunction with phosphate and/or oxalates, and are particularly preferred, and these chemical compounds are in conjunction with phosphate ion.In order to illustrate, will be to being described in conjunction with anionic chemical compound, particularly chemical compound in conjunction with phosphate ion; But, be understandable that by being conspicuous suitable change for those of ordinary skills, this description is equally applicable to other ion and solute.Chemical compound can coupled ion, as anion, when they and ion link together, usually need not to be non-covalent mode, under enough association intensity, ionic at least a portion keeps combination in vivo or under the external condition, and wherein said polymer is used time enough, to reach in body or the effect of deionizing the solution.Object ion can be the bonded ion of described chemical compound, and it is commonly referred to as following ion, thereby chemical compound and such ions binding produce the therapeutic effect of chemical compound, and it can be anion or cation.Chemical compound of the present invention can have more than one object ion.

For example, polymer more of the present invention have shown in conjunction with phosphatic performance.In conjunction with phosphatic ability is to weigh phosphate binders amount in conjunction with phosphate ion in given solution.For example, can be in the binding ability of testing in vitro phosphate binders, as in water or in the saline, testing; Or test in vivo, as the phosphaturia Excreta; Or test indirectly in vivo, test as the liquid of use extracting out, for example the chyme that obtains in animal, human body or the volunteer's body.Test can be carried out in the solution that only contains phosphate ion, perhaps carries out under situation about existing less than the competition solute with phosphate ion competition conjugated polymer resin at least.In these cases, can use non-interference buffer.Selectable, described test can be carried out under the situation that has other competition solute, as other ion or metabolite, and described competition solute and phosphate ion (target solute) competition binding resin.

The compound ions binding ability can be tested as shown in example.The phosphate binding ability of some embodiments is greater than about 0.2,0.5,1.0,1.5,2.0,2.5,3.0,3.5,4.0,5.0,6.0,8.0,10.0,12,14,16,18mmol/g, or greater than about 20mmol/g.In some embodiments, The compounds of this invention greater than about 0.5mmol/g, is preferably greater than about 2.5mmol/g, more preferably greater than about 3mmol/g to the external phosphate binding ability of object ion, be preferably greater than about 4mmol/g especially, further be preferably greater than about 6mmol/g.In some embodiments, the scope of described phosphate binding ability arrives about 20mmol/g for about 0.2mmol/g, and for example, about 0.5mmol/g is to about 10mmol/g, and preferably about 2.5mmol/g is to about 8mmol/g, and more preferably from about 3mmol/g is to about 6mmol/g.

In some embodiments, The compounds of this invention and compositions can reduce the phosphorus of 5-100% in the patient's urine that need treat, as 10-75%, 25-65% or 45-60%.Some embodiments can make the phosphorus in the urine reduce greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 45%, greater than 50% or greater than 60%.

Many technology known in this field can be used for measuring the phosphate binding ability.The suitable technique example describes in the following embodiments.

When crosslinked, some embodiments of The compounds of this invention form colloid in solvent, as form colloid in simulation intestines and stomach medium or physiology acceptable medium.

Hud typed compositions

On the one hand, the present invention relates to contain the hud typed compositions of polymer core and shell.In some embodiments, described polymer core comprises cross linked polymer of the present invention.Described shell matter can be by chemical anchoring or physics coating to nuclear matter.In the previous case, described shell can grow on nuclear consitution by chemical mode, as passes through: from anchoring to the avtive spot on the nuclear polymer, by living polymerization with the shell polymeric chemical graft to nuclear; Interfacial reaction promptly is positioned at the chemical reaction on nuclear particle surface, as the interfacial polycondensation effect; And when nuclear particle is synthetic, use block copolymer as suspending agent.

When using chemical method, preferably use interfacial reaction and block copolymer.In the method for interfacial reaction, usually, the periphery of nuclear particle carries out chemical modification by micromolecule or macromolecular reaction on the nuclear interface.For example, the amine that contains the ions binding nuclear particle reacts to form crosslinked shell around nuclear with the polymer that contains amino-reactive group (as epoxy resin, isocyanates, reactive resin, halide group).

In another embodiment, at first make the shell of capsule shape with interfacial polycondensation effect or solvent cohesion.Capsular inboard becomes precursor to fill with karyomorphism subsequently, thereby forms nuclear in the shell capsule.

In some embodiments, with the method for block copolymer, amphiphilic block copolymer as suspending agent, is formed nuclear particle in anti-phase or direct particle formation technology.When using anti-phase Water-In-Oil suspension process, described block copolymer comprises first block that dissolves in the oil-continuous phase, and another hydrophilic block comprises the functional group with the nuclear polymer reaction.When become precursor with karyomorphism, when oil phase is added to aqueous phase, described block copolymer is positioned on the Water-In-Oil interface, and as suspending agent.Hydrophilic block and nuclear matter react, or become precursor one to react with karyomorphism.After granule separated from oil phase, described block copolymer formed and the covalently bound shell in nuclear surface.The chemical property of described block and length can change, to change shell to interested solute penetration performance.

When shell material to nuclear matter the time, can be used known microencapsulation technology by physical absorption, as solvent cohesion, bed spray coater or multistage emulsion technology.The method for optimizing of microencapsulation is the bed spray coater in the Wurster structure.In another embodiment, when in mouth and esophagus, shell material only works by the expansion that delays nuclear particle temporarily, and optionally decomposes in stomach or duodenum.Then, enter in the nuclear particle, select shell by producing high hydrophobicity and very low liquid water permeability layer in order to stop water.

In one embodiment, shell material has negative charge in environment for use.Be not limited to a kind of reaction mechanism, it is generally acknowledged, be coated in anion and strengthened combining of little inorganic ions and low charge density (as phosphate) in conjunction with the electronegative shell material on the pearl, this combination has surpassed the competing ions that has than thick atom valency or size.Therefore, competitive anion (as citrate, cholic acid and fatty acid etc.) has the relative affinity less to the anion syncaryon, and this may be because competing ions passes the limited institute of the penetrating power of shell causes.

Preferred shell matter is an electronegative polymer under general enteral pH scope.Example includes but not limited to: have the polymer of acid groups side group, described acid groups is for example carboxyl, sulfonic group, hydrogenation sulfonic group, sulfamide groups, phosphate, hydrogen phosphide acidic group, phosphonate group, phosphine hydracid base, phosphoramidic acid base, anthracites acidic group, boronate and its combination.Described polymer can be protonated or non-protonization; In the latter, acidic anionic can neutralize with pharmaceutically acceptable cation, as Na, K, Li, Ca, Mg and NH ₄

In another embodiment, the form that polyanion can precursor is used, and the final activation of described precursor is polyanion; For example, poly-sulfonic acid or some unstable ester of polycarboxylic acids or the form of anhydride are easy to hydrolysis under the sour environment of stomach, and can change into active anion.

Shell polymeric can be linear, branching, hyperbranched, sectional (being trunk polymer is arranged in order by the contiguous block that contains a sour side group at least), pectination, starlike or crosslinked net, fully and half inner inierpeneirating network structure (IPN).Shell polymeric in the compositions be at random or block, but and covalency or physical bond to nuclear matter.The example of this shell polymeric includes but not limited to acrylate homopolymer or copolymer, methacrylic acid homo thing or copolymer, and the copolymer of acrylic acid methyl ester. and methacrylic acid.The example of this polymer is the copolymer of copolymer, ethyl propylene acid esters and the methacrylic acid of methyl methacrylate and methacrylic acid, and its commercially available commodity are called Eudragit (Rohm GmbH﹠amp; Co.KG); Its example comprises Eudragit L100-55 and Eudragit L100 (methyl methacrylate-methacrylic acid (1: 1) copolymer, Degussa/Rohm), Eudragit L30-D55, Eudragit S 100-55 and Eudragit FS 30D, Eudragit S 100 (methyl methacrylate-methacrylic acid (2: 1) copolymer), Eudragit LD-55 (ethylacrylic acid methyl ester-methacrylic acid (1: 1) copolymer), have the acrylate of quaternary ammonium group and the copolymer of acrylic acid methyl ester., its commercially available commodity Eudragit RL by name and Eudragit RS; And without any the neutral esters dispersant of functional group, its commercial goods is called Eudragit NE30-D.

Other shell polymeric comprises: poly-(styrene sulfonate),

Polyacrylic acid, carboxymethyl cellulose, cellulosic phthalic acetate, commercially available commodity HP-52 by name and HP-55 (Shin-Etsu Chemical Co., Ltd) HYDROXY PROPYL METHYLCELLULOSE phthalic acid ester, cellulose acetate trimellitic acid ester, cellulose ethanoate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, cellulose derivative, as hydroxypropyl emthylcellulose, methylcellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, hydroxyethyl ethylcellulose, and Cellulose ethyl hydroxypropyl ether, and cellulose derivative, as be used for the cellulose esters of coating parcel preparation, polyethylene acetic acid phthalic acid ester, carrageenin, alginate esters, or poly-(methacrylic acid) ester, acrylic acid/maleic acid, styrene/maleic acid, itaconic acid/acrylic copolymer, and fumaric acid/acrylic copolymer, the commercial goods is called AEA (Sankyo Co., Ltd) polyvinyl acetal diethylamide acetas, methyl ethylene ester/maleic acid and lacca.

In some preferred embodiments, shell polymeric is selected from pharmaceutically acceptable polymer, as Eudragit L100-55 and Eudragit L100 (methyl methacrylate-acrylic acid (1: 1) copolymer, Degussa/Rohm), Carbopol 934 (polyacrylic acid, Noveon), C-A-P NF (the cellulose ethanoate phthalic acid ester--Estman), Eastacryl (methacrylate--Estman), carrageenin and Alginate (FMC Biopolymer), Anycoat-P (Samsung Fine Chemicals--HPMCPhthalate) or Aqualon (carboxymethyl cellulose, Hercules), methyl ethylene ester/maleic acid (Gantrez), and styrene/maleic acid (SMA).

Described shell can apply by several different methods.In one embodiment, described shell material adds as active excipient in the pharmaceutical preparation step; For example, described shell material can be used as powder packets and is contained in the solid preparation, and itself and phosphate-binding polymers carry out physical mixed with other excipient, selectively grind, and compacting forms tablet.Thereby in some embodiments, in drug products, shell matter does not need to cover nuclear matter.For example, acid shell polymeric can add with anion syncaryon polymer, be mixed with forms such as tablet, capsule, gel, liquid, then, thin film, extrudate and shell polymeric solubilized and homodisperse are as the shell coating round nuclear, simultaneously medicine in the mouth, esophagus or finally at action site, i.e. gastrointestinal tract place equilibrium.

In some embodiments, described shell is the shell polymeric layer.This layer is the molecular layer of the lip-deep polyanion of nuclear particle.And the weight ratio of nuclear is between about 0.0001% to about 30%, between preferred about 0.01% to about 5%, according to appointment between 0.1% to about 5%.

Preferably, described shell polymeric reduces molecular weight with minimizing, thus shell polymeric can free permeation in the nucleopore crack, can be from not examining surperficial eluting yet.Preferably, the molecular weight of shell acid polymer is about 1000g/mol, is more preferably about 5000g/mol, and is preferred especially about 20,000g/mol.

The anionic charge density of shell material (accounting for leading in applied environment) between 0.5 to 22mEq/gr, is preferably 2mEq/gr to 15mEq/gr.If coating process is used for forming the part that shell is produced as dosage form on polymer beads, then the known technology of the those of ordinary skill in the pharmaceutical industry field can be used.In preferred embodiments, described shell is gone up at fluid bed coater (Wurster coater) and is formed.In optional embodiment, described shell forms by controlled precipitation or cohesion, and wherein polymer beads is suspended in the polymer solution, and changes the performance of solvent in this way, thereby induced polymer precipitation or coating are to polymer beads.

Suitable coating compounds technology is included in technology commonly used in the pharmaceutical industry.General, a plurality of parameters are depended in the selection of coating process, include but not limited to: the formation of shell material (body, solution, emulsion, suspension, melt), and the amount of the shape of nuclear material (spherical bead, irregular shape etc.) and performance, sedimentary shell.In addition, endorse with one or more shell coatings, and can comprise a plurality of or alternative coating of shell.

The treatment of unbalance disorder of phosphate and nephropathy

The term " the unbalance disorder of phosphate " that the present invention uses is meant the abnormal symptom of phosphorus level that exists in the body.An example of the unbalance disorder of phosphate comprises hyperphosphatemia.The term " hyperphosphatemia " that the present invention uses is meant that the interior P elements of body is in the symptom of an elevated levels.General, if the serium inorganic phosphorus level is for being higher than about 4.0 or 4.5 milligrams/deciliter (mg/dl) in the blood, for example be higher than about 5.0mg/dl, for example be higher than about 5.5mg/dl, for example be higher than 6.0mg/dl, and/or the glomerulus filtering rate descends, and for example surpasses approximately 20%, and the patient usually is diagnosed as hyperphosphatemia.The present invention can be used for also treating that End Stage Renal Disease suffers from hyperphosphatemia and it is accepting the patient of dialysis treatment (as hemodialysis or peritoneal dialysis).

Can comprise with other disease of method of the present invention, compositions and test kit treatment: the heterotopic calcification of the tetany that the kidney of hypocalcemia, hyperparathyroidism, repressed calcitriol is synthetic, hypocalcemia causes, renal insufficiency, cartilaginous tissue, it is included in the calcification of joint, lung, kidney, conjunctiva and cardiac muscular tissue.In addition, the present invention also can be used for the treatment of chronic nephropathy (CKD), End Stage Renal Disease (ESRD) and dialysis patient, comprises the prophylactic treatment of above-mentioned arbitrary symptom.

The adminicle that polymer of the present invention, chemical compound and compositions also can be used as other treatment uses, as is used for absorption, dialysis inorganic metal salt and/or other fluoropolymer resin of diet control phosphorus.

Compositions of the present invention also is used for removing chloride, heavy carbonate, oxalates and cholic acid from intestines and stomach.The polymer that oxalate ion is removed in discovery can be used for treating the unbalance disorder of oxalates, as increasing oxalic acid increase disease and the oxalates urine that renal calculus forms risk.The polymer that chloride ion is removed in discovery for example can be used for treatment, acidosis, heartburn, sour adverse current disease, sour stomach or gastritis.In some embodiments, compositions of the present invention is used to remove fatty acid, bilirubin and relevant chemical compound.Some embodiments also can in conjunction with and remove high-molecular weight molecule, as protein, nucleic acid, vitamin or cell debris.

The invention provides method, pharmaceutical composition and the test kit of treatment animal.Term " animal " or " animal recipient " or " patient " that the present invention uses comprise the people, and other mammal (for example in veterinary treatment, be used for the treatment of Canis familiaris L. or cat, or domestic animal, as pig, sheep, cattle, horse, chicken and similar animal).One embodiment of the invention are that crosslinked aminated compounds by using at least a treatment effective dose of the present invention is to remove the phosphatic method in the animal gastrointestinal tract.

The term " treatment " that the present invention uses and its phraseological synonym comprise acquisition therapeutic effect and/or preventive effect.For therapeutic effect, its implication is for eradicating, improve or prevent following disease of being treated.For example, for the hyperphosphatemia patient, therapeutic effect comprises elimination or improves described hyperphosphatemia.And therapeutic effect also can be by elimination, improvement or prevention one or more physiological signs relevant with following disease, thereby observe improvement in the patient, though the patient may still suffer the torment of described disease.For example, the patient who suffers from renal insufficiency and/or hyperphosphatemia is used crosslinked amine polymer of the present invention, not only produced the therapeutic effect that patients serum's phosphorus level is descended, and, observe improvement among the patient as heterotopic calcification and osteodystrophy suffering from other relevant disease of renal insufficiency and/or hyperphosphatemia.For preventive effect, for example, even without the diagnosis of carrying out hyperphosphatemia, also the patient of the physiological signs that can one or more hyperphosphatemias be arranged to patient that development hyperphosphatemia risk is arranged or report uses crosslinked amine polymer.

Compositions also can be used for controlling the serum paraoxonase of the receptor with rising phosphate level, for example, by phosphatic serum levels being adjusted to normal or near normal level, for example the healthy patients normal level 10% within.

Usually, described chemical compound can be in ante cibum or is used after meal, or uses when having a meal.As using among the present invention, meal " preceding " or meal " back " within two hours, preferably within one hour, are more preferably within 30 minutes usually, and be preferred especially respectively within beginning to have meal or finishing 10 minutes of dining.

One embodiment of the invention relate to pharmaceutical composition, described pharmaceutical composition contains at least a chemical compound or described chemical compound pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipient, diluent or carrier and selectable other therapeutic agent.Described chemical compound can be freeze dried before preparation, or exsiccant in vacuum or stove.

Described excipient or carrier are " acceptable ", and the meaning is that it can be compatible with other composition of preparation, can't be harmful to the receptor.Described preparation can be made unit dosage forms easily, and can be prepared with any suitable method.Method generally includes medicament and excipient or the blended step of carrier, as polymer is mixed equably and fully with excipient or carrier, if necessary, again with its unit dosage forms of production sharing.

Pharmaceutical composition of the present invention comprises such compositions, and wherein said crosslinked amine polymer exists with effective dose, promptly can obtain the effective dose of therapeutic effect and/or preventive effect.Actual effective dose in concrete the application depends on the status of patient (as age, body weight) of being treated, and route of administration.

In the animal dosage of aminated compounds or polymer depend on the disease of being treated, route of administration, the health of the animal treated.In some embodiments, this class dosage level that treats and/or prevents purposes can be about 1gm/ days to about 30gm/ days, for example about 2gm/ days to about 20gm/ days, or about 3gm/ days to about 7gm/ days.The dosage of chemical compound described in the present invention and polymer can be less than about 50gm/ days, less than about 40gm/ days, and less than about 30gm/ days, less than about 20gm/ days, and less than about 10gm/ days.Usually, preferred described aminated compounds or polymer are edible with food.Described polymer can use once a day, one day twice, one day three times.Preferably, described chemical compound is used once a day with the feed of maximum.

Preferably, described aminated compounds and polymer can be used for the treatment of and/or preventive effect, and can use separately or use with the form of pharmaceutical composition.Described pharmaceutical composition contains aminated compounds and/or polymer, one or more pharmaceutically acceptable carriers, diluent or excipient, and selectable other therapeutic agent.For example, according to the disease of being treated, aminated compounds of the present invention and/or polymer can be used with other active pharmaceutical agent.The example of the pharmaceutical preparation that can use together includes but not limited to:

Be suitable for the pharmaceutically acceptable lanthanum of other phosphate chelating agen of the present invention, calcium, aluminum, magnesium and zinc compound, for example acetate, carbonate, oxide, hydroxide, citrate, alginate, and keto acid.

Calcium compounds (comprise calcium carbonate, calcium acetate (as

Calcium acetate tablet), calcium citrate, calcium alginate and calcium picrolonate) be used for phosphatic combination.The calcium of picked-up combines with phosphate, forms insoluble calcium phosphate, as Ca ₃(PO ₄) ₂, CaHPO ₄Or Ca (H ₂PO ₄) ₂

Based on the phosphate chelating agen of aluminum, as

Alumine hydroxide colloid also has been used for the treatment of hyperphosphatemia.These chemical compounds and intestinal phosphate are compounded to form highly insoluble aluminum phosphate, and bonded phosphate can not be absorbed by the patient.

The most frequently used lanthanide series compound, lanthanum carbonate (

) similar with the effect of calcium carbonate.

Be suitable for other phosphate chelating agen of the present invention and comprise pharmaceutically acceptable magnesium compound.The different instances of pharmaceutically acceptable magnesium compound is on the books in the U.S. Provisional Application of submitting on November 8th, 2,005 60/734,593, and it is all instructed and incorporates the present invention into as a reference.Concrete suitable example comprises: the acylate of the alkoxide (as Diethoxymagnesium and magnesium isopropoxide) of magnesium oxide, magnesium hydroxide, magnesium halide (as Afluon (Asta), magnesium chloride, magnesium bromide and magnesium iodide), magnesium, magnesium carbonate, magnesium bicarbonate, magnesium formate, magnesium acetate, trisilicate, magnesium, as fumaric acid, maleic acid, acrylic acid, methacrylic acid, itaconic acid and styrene sulfonic acid, and combination.

The various examples of pharmaceutically acceptable zinc compound illustrate that it is all instructed and incorporates the present invention into as a reference in the PCT application PCT/US2005/047582 of December in 2005 submission on the 29th.The concrete suitable example of pharmaceutically acceptable zinc compound comprises: zinc acetate, zinc bromide, zinc octoate, zinc carbonate, zinc chloride, zinc citrate, zinc formate, Zinc Fluosilicate, zinc iodate, zinc iodide, the starch zinc iodide, zinc lactate, zinc nitrate, zinc oleate, zinc oxalate, zinc oxide, smithsonite (zinc oxide that the sub-fraction ferrum oxide is arranged), the p-zinc sulfocarbolate, zinc propionate, zinc salicylate, zinc silicate, zinc stearate, zinc sulfate, zinc sulfide, tannin zinc, zinc tartrate, zinc valerate and ethylene two (aminodithioformic acid) zinc.Another embodiment comprises poly-(zinc acrylate resin).

When being referenced to above-mentioned any phosphate chelating agen, be understandable that, in its mixture, polymorph or solvate are included in.

In some embodiments, the mixture of above-mentioned phosphate chelating agen can be united use with pharmaceutically acceptable iron salt in the present invention.

In other embodiment, the phosphate chelating agen of uniting use with The compounds of this invention is not pharmaceutically acceptable magnesium compound.In other embodiments, the phosphate chelating agen with pharmaceutically acceptable aminated compounds and/or combination with polymers use is not pharmaceutically acceptable zinc compound.

The present invention also comprises the method and the pharmaceutical composition of therapeutic alliance, and wherein aminated compounds and/or polymer and phosphate cotransporter inhibitor, HMG-CoA reductase inhibitor such as inhibin or alkaline phosphatase enzyme inhibitor are united use.Selectable, aminated compounds and/or mixture of polymers can be used together with phosphate cotransporter inhibitor, HMG-CoA reductase inhibitor such as inhibin or alkaline phosphatase enzyme inhibitor.

The suitable example of phosphate cotransporter inhibitor is seen common application 2004/0019113,2004/0019020 co-pending of the U.S. and International Application No. WO 2004/085448, and whole instructions of these applications are included into the present invention as a reference.

The suitable example of the HMG-CoA reductase inhibitor in the therapeutic alliance of the present invention comprises: lovastatin (mevinolin) (as

With

) and related compound; Pravastatin (as

With

) and related compound; Simvastatin (as

And related compound.Can be used for other HMG-CoA reductase inhibitor of the present invention comprise fluvastatin (as

), cerivastatin (as

With

), atorvastatin (as

With

), Pitavastatin, Rosuvastatin (visastatin) (as

), quinoline, mevalonolactone analog and derivant thereof are (with reference to United States Patent (USP) 5,753,675, it is all instructed and includes the present invention in as a reference), pyrroles's analog of mevalonolactone derivant is (with reference to United States Patent (USP) 4,613,610, it is all instructed and includes the present invention in as a reference), the indenes analog of mevalonolactone derivant is (with reference to WO 86/03488, it is all instructed and includes the present invention in as a reference), 6-[2-(pyrroles of replacement-1-yl)-alkyl) pyran-2-one and derivant thereof are (with reference to United States Patent (USP) 4,647,576, it is all instructed and includes the present invention in as a reference), the imidazoles analog of mevalonolactone is (with reference to WO 86/07054, it is all instructed and includes the present invention in as a reference), 3-hydroxyl-4 (dihydroxy oxo phosphorus) butanoic acid derivative is (with reference to French Patent (FRP) 2,596,393, it is all instructed and includes the present invention in as a reference), the naphthyl analog of mevalonolactone is (with reference to United States Patent (USP) 4,686,23, it is all instructed and includes the present invention in as a reference), the octahydro naphthalene is (with reference to United States Patent (USP) 4,499,289, it is all instructed and includes the present invention in as a reference), and quinoline and pyridine derivate are (with reference to United States Patent (USP) 5,506,219 and 5,691,322, it is all instructed and includes the present invention in as a reference).Preferred inhibin is as atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, Rosuvastatin, cerivastatin and pravastatin.

A large amount of organic and inorganic molecules is alkali phosphatase (ALP) inhibitor (for example, with reference to United States Patent (USP) 5,948,630, it is all instructed and includes the present invention in as a reference).The example of alkaline phosphatase enzyme inhibitor comprises orthophosphate, arsenate, L-phenylalanine, L-homoarginine, tetramisole, levamisole, L-p-bromine tetramisole, 5,6-dihydro-6-(2-naphthyl) imidazo-[2,1-b] thiazoles (naphthyl) and derivant thereof.Preferred inhibitors includes but not limited to: levamisole, bromine tetramisole and 5,6-dihydro-6-(2-naphthyl) imidazo-[2,1-b] thiazole and derivant thereof.

Co-administeredly can comprise two kinds of reagent using simultaneously in the same dosage form, be applied in two kinds of reagent in the dosage form separately simultaneously, and use respectively.For example, for the treatment of hyperphosphatemia, crosslinked amine polymer can be used with the calcium salt that is used for the treatment of the hypocalcemia that is caused by hyperphosphatemia.

Medicine of the present invention can be mixed with tablet, XIANGFEN, slurry, food formulation, tablet, capsule, elixir, suspension, syrup, disk, chewing gum or lozenge.

Preferably, described aminated compounds or polymer, or contain the pharmaceutical composition of aminated compounds or polymer can be Orally administered.The example of suitable method, medium, excipient and carrier is at Remington ' s Pharmaceutical Sciences, and 18 editions, in (1990) explanation is arranged, its content is included into the present invention as a reference.

Can adopt one or more physiology acceptable carriers to prepare with conventional method according to pharmaceutical composition used in the present invention, described carrier contains and helps reactive compound to be formulated into adjuvant and excipient in the medicinal preparation.Suitable dosage form depends on the selection of route of administration.The suitable method of preparation amine drug compositions is well known in the art.

In some embodiments, polymer of the present invention provides with the pharmaceutical composition of chewable tablet form.Except active component, can use the excipient of following type usually: the sweeting agent of necessary taste and the binding agent that uses are provided, reduce die wall friction power effect and are convenient to the lubricant that tablet is extruded under the situation that enough tablet hardnesses can not be provided; And in some preparations, add a spot of disintegrating agent and be convenient to chew.Usually, in the chewable tablet the present level of excipient be active component 3-5 doubly, wherein sweeting agent has accounted for a large amount of non-active ingredients.

In schemes more of the present invention, the intensity and the hot property that are provided by excipient usually are provided described polymer, have therefore reduced the amount of this required class excipient in the dosage form.In some embodiments, described polymer or component are formed and are surpassed about 30wt.% in the compositions, for example, surpass about 40wt.%, surpass about 50wt.%, preferably surpass about 60wt.%, surpass about 70wt.%, be more preferably and surpass about 80wt.%, surpass about 85wt.% or, remaining comprise suitable excipient above about 90wt.%.

In some embodiments, the compressibility of tablet depends primarily on the degree of hydration (moisture) of chemical compound or polymer.Preferably, the moisture of described polymer or chemical compound accounts for the 5wt% of weight or more, is more preferably, and moisture accounts for the 5wt.% of weight to about 9wt.%, most preferably, accounts for the 7wt.% of weight.Should be appreciated that, polymer by the embodiment of hydration in, the water of hydration is considered to the component of polymer.

Described tablet can further contain one or more excipient well known in the art, as firming agent, fluidizer and lubricant.Suitable excipient comprises silicon dioxide colloid, stearic acid, magnesium silicate, calcium silicates, sucrose, calcium stearate, Tridocosanoin, magnesium stearate, Muscovitum, zinc stearate and sodium stearyl fumarate.

Tablet core in the embodiment of the present invention can prepare with the method that comprises the steps: (1) is with aliphatic amine polymer aquation or dry to obtain required moisture; (2) with polymer and any mixed with excipients; And (3) use conventional pressed-disc technique compressed mixture.

In some embodiments, the present invention relates to stable, deglutible coated tablet, particularly contain the tablet of suction nuclear, such as, the aforesaid tablet that contains polymer.In one embodiment, described coating composition contains cellulose derivative and plasticizer.Cellulose derivative is preferably HYDROXY PROPYL METHYLCELLULOSE (HPMC).Cellulose derivative can be the form of aqueous solution.Suitable HYDROXY PROPYL METHYLCELLULOSE solution comprises the solution that contains low viscosity HPMC and/or high viscosity HPMC.Other suitable cellulose derivative comprises the cellulose ether that is used for the film coating preparation.Plasticizer for example can be, acetylizad monoglyceride is as the monoglyceride of diacetylation.Described coating composition further comprises the pigment of selecting to be used to provide the tablet coating with desired color.For example, for white coating is provided, select the pigment of white, as titanium dioxide.

In one embodiment, coated tablet of the present invention is prepared by the method that comprises following steps: as mentioned above, tablet core of the present invention is contacted with the coating solution that contains solvent, wherein at least a coating reagent is dissolved in or is suspended in solvent, and, selectable, in one or more plasticizers.Preferably, described solvent is the aqueous solution solvent, as water or aqueous solution buffer, or blended aqueous solution/organic solvent.Preferred coating reagent comprises cellulose derivative, as HYDROXY PROPYL METHYLCELLULOSE.Usually, tablet core contacts with coating solution, is increased to about weight range of 4% to 6% until the weight of tablet core, and this shows that depositing to of suitable coating formed coated tablet on the tablet core.

The drug excipient that uses in other some compositions of the present invention comprises: binding agent, as microcrystalline Cellulose, carbopol, polyvidone and xanthan resin; Flavoring agent is as mannitol, sorbitol, maltodextrin, fructose or xylitol; Lubricant, as derive from the fatty acid of vegetable; And selectable, disintegrating agent is as sodium cellulosate, gellan gum resin, cellulosic low substituted hydroxy-propyl ether, Sodium Starch Glycolate.These additives and other appropriate ingredients are well known in the art, for example, with reference to Gennaro A R (ed), Remington ' s Pharmaceutical Sciences, the 20th edition.

In some embodiments, pharmaceutical composition provided by the invention is formulated into chewable tablet, contains polymer of the present invention and suitable excipient in the described chewable tablet.In some embodiments, pharmaceutical composition provided by the invention is formulated into chewable tablet, contains polymer of the present invention, filler and lubricant in the described chewable tablet.In some embodiments, pharmaceutical composition provided by the invention is formulated into chewable tablet, contain polymer of the present invention, filler and lubricant in the described chewable tablet, wherein said filler is selected from sucrose, mannitol, xylitol, maltodextrin, fructose and sorbitol, wherein said lubricant is a fatty acid magnesium salt, as magnesium stearate.

In one embodiment, described polymer and high Tg/ high-melting-point, low-molecular-weight excipient are mixed with solid solution together in advance as mannitol, sorbose, sucrose, and wherein said polymer and excipient fully mix.Blended method all is available as extruding, spray drying, cool-drying (chill drying), lyophilization or wet grinding.Public by known physical method, show blended degree as differential scanning calorimetry or dynamic mechanical analysis.

In some embodiments, polymer of the present invention provides with the pharmaceutical composition of liquid preparation form.In some embodiments, described pharmaceutical composition contains the polymer that is scattered in the suitable liquid excipient.Suitable liquid excipient is well known in the art, as Remington ' s PharmaceuticalSciences.

In some embodiments, the powder dosage form that described pharmaceutical composition can be packaged into pouch provides, its can with water or other ingestible liquid mixing, and Orally administered as beverage (solution or suspension).Provide patient acceptable character in order to ensure this class preparation, for example mouthfeel and taste, pharmaceutically acceptable anionic stabilizer can be included in the preparation.

The example of suitable anionic stabilizer comprises: anionic polymer, as anion polypeptide, anion polysaccharide, the perhaps polymer of one or more anionic monomers is as mannuronic acid, guluronic acid, acrylic acid, methacrylic acid, glucuronic acid, glutamic acid or its combination of polymers; And pharmaceutically acceptable salt.Other example of anionic polymer comprises cellulose, as carboxyl alkyl cellulose or pharmaceutically acceptable salt.Anionic polymer can be the copolymer of homopolymer polymer or above-mentioned two or more anionic monomers.Selectable, described anionic copolymer comprises one or more anionic monomers, and one or more neutral comonomers, as the alkene anionic monomer, as vinyl alcohol, acrylamide and ethylene carboxamide.

The example of anionic polymer comprises alginate (as sodium alginate, potassium alginate, calcium alginate, alginic acid magnesium, aluminium alginate and alginic acid ester), carboxymethyl cellulose, polylactic acid, polyglutamic acid, pectin, xanthan gum, carrageenin, Furcellaran calcium, Radix Acaciae senegalis, karaya, gum ghatti, tracasol and Huang Jing glue.The preferred anionic surfactants polymer is an alginate, and is preferably esterified alginate salt, as the C2-C5-diol ester of alginate or C3-C5-three alcohol esters of alginate." the esterified alginate salt " that uses among the present invention is meant the esterified alginic acid of wherein one or more carboxyls.The carboxyl that is left in the alginate optionally is neutralized (partly or entirely) and is pharmaceutically acceptable salt.For example, the propylene glycol alginic acid ester is the ester of alginic acid, the propylene glycol esterification of some of them carboxyl, and remaining carboxyl optionally neutralizes with pharmaceutically acceptable salt.Be more preferably, described anionic polymer is the ethylene glycol alginic acid ester, propylene glycol alginic acid ester or glycerol alginic acid ester, and wherein the propylene glycol alginic acid ester is more preferably.

All open source literatures mentioned in this description and the equal integral body of patent application are incorporated the present invention into as a reference, and its degree is incorporated the present invention into as a reference individually as every piece of open source literature or patent application.

To those skilled in the art, to the modification of the disclosure of invention or change purport and the scope that does not also deviate from claims of the present invention.

Embodiment

Use as the present invention, unless say especially, following term has specified implication.

DAB-4:1,4-two [two (3-aminopropyl) amino] butane, it can be buied from Aldrich.

DAB-8:1,4-two (two (3-(two (3-aminopropyl) amino) propyl group) amino) butane, it can be buied from SyMO-Chem.

DAB-16:1,4-two [two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] butane, it can be buied from SyMO-Chem.

DAB-32:1,4-two [two [3-[two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] propyl group] amino] butane, it can be buied from SyMO-Chem.

DAB-64:1,4-two [two [3-[two [3-[two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] propyl group] amino] propyl group] amino] butane, it can be buied from SyMO-Chem.

PAMAM: amide ehtylethanolamine tree and 1,20% methanol solution of 4-diaminobutane nuclear, it can be from Dendritic NanoTechnologies, and Inc buys, i.e. DNT-103.

DAP-Am-4:N, N, N ', N '-four (3-aminopropyl)-1, the 3-propane diamine, it can be from PolyOrg, and Inc buys.

EPI: epoxychloropropane, it can be buied from Aldrich.

Poly-(epoxychloropropane): it can be buied from Aldrich.

TCA: three (2-dichloroethyl ether) amine, it can be buied from Aldrich.

DBE:1, the 2-Bromofume, it can be buied from Aldrich.

BDDE:1, the 4-butanediol diglycidyl ether, it can be buied from Aldrich.

External phosphate combination: refer to following method.

Expansion rate in the technical process: refer to following method.

Embodiment 1-47

Under the room temperature, choose wantonly under blanket of nitrogen, stir the solution of amine and solvent, and add cross-linking agent formation colloid, prepare the amine polymer of embodiment 1-47.After at room temperature cooling off and solidifying, colloid is dispersed into little fragment, and is suspended in water or the methanol, stir, filter.Selectable, the pH value of solution is suitably regulated with spissated HCl.Filtering solution then.The polymer of washing is dry under 60 ℃ in the forced ventilation baking oven, to obtain the dry weight of polymer.

Table 1-10 provide component and amount concrete among the embodiment 1-47.Simultaneously, external phosphate binding data and expansion rate are also listed among the table 1-10 among some embodiment.Table 11-28 provide reductive data in the urine phosphate body.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Embodiment 48-82

Embodiment 48

Adding spissated HCl (9.5ml) in deionized water (40ml) solution of DAB-16 (10.33g), is 8.1 until the pH of solution.With the solution lyophilizing, obtain 11.9 grams.

Embodiment 49

DAB-8 (7.18g), formic acid (35g 88% aqueous solution) and formaldehyde (aqueous solution of the 37wt% of 18.11g) were 80 ℃ of heating 24 hours.Behind the cool to room temperature, adding 50% NaOH aqueous solution in reactant mixture, is 13.5 until the pH of reactant mixture, then adds deionized water (30ml).With dichloromethane extraction reactant mixture (3 * 170ml).The dichloromethane extraction liquid that merges is with dried over sodium sulfate, filtration, and concentrates with rotary evaporator, obtains the grease of 8.46g.Analyze and find: C, 62.78; H, 12.21; N, 17.84.

Embodiment 50

In the stirring the mixture of DAB-8 (4g), dichloromethane (250mL) and sodium bicarbonate (14.5g), add in the chloroacetic chloride (3.57g).After stirring is spent the night, form solid.Dichloromethane layer is inclined to, and solid residue is dissolved in deionized water (300mL), adding 50% NaOH is 13 until pH.(3 * 200mL) wash this solution with dichloromethane.Water layer concentrates with rotary evaporator, and precipitates by adding methanol.Solution is filtered, and concentrate with rotary evaporator.In residue, add methanol (100mL), and mixture is stirred 32h, filter then.Solution after filtering is concentrated with rotary evaporator.Residue is diluted with dichloromethane (130mL).Filtering mixt, and the solution after will filtering concentrates with rotary evaporator.Residue is used dichloromethane (130mL) dilution once more.Filter this mixture, and the solution after will filtering is concentrated with rotary evaporator, obtains 9.3g.

Embodiment 51

In 90 fens clock times, with spissated HCl (104.10g) join DAB-4 (167.2g, 0.528mol) in, it cools off in ice bath, keeps the temperature of DAB-4 solution to be lower than 10 ℃.In independent flask, DBSA, sodium chloride (30.8g) and deionized water (71.87g) are heated to 60 ℃, continue 20 minutes, until whole dissolvings.DBSA and sodium chloride solution are joined in the DAB-4 solution.Under blanket of nitrogen, the solution that obtains is joined in the toluene (1086g), and with mixture heated to 80 ℃.Under stirring fast, (103.25mL, 122.14g, toluene solution 1.32mol) (155mL) dropwise added in two hour time with EPI.After the adding, reactant was further heated 6 hours at 80 ℃, and cool to room temperature.Filter reaction mixture.The solid suspension of collecting stirred 20 minutes in methanol (2L), and filtered.This methanol wash repeats twice.Solid suspension after filtering in 20% NaOH (2L) aqueous solution, was stirred 20 minutes, and filter.This NaOH of 20% (2L) solution washing repeats twice.Solid suspension after the filtration stirred 20 minutes in methanol (2L), and filtered.This methanol wash repeats once.Solid suspension after the filtration stirred 20 minutes in deionized water (4L), and filtered.This deionized water wash repeats twice.Polymer (weight in wet base is 759.54g) after lyophilizing is filtered obtains 192.66g.Expansion rate in the technical process is 3.15mL/g.The external phosphate of 1 hour and 5 hours is in conjunction with being respectively 0.86mmol/g and 0.74mmol/g.

Embodiment 52

In 90 fens clock times, with spissated HCl (12.5mL) join DAB-4 (20g, 0.0632mol) in, it cools off in ice bath, keeps the temperature of DAB-4 solution to be lower than 10 ℃.In independent flask, DBSA, sodium chloride (30.8g) and deionized water (71.87g) are stirred, until whole dissolvings.DBSA and sodium chloride solution are joined in the DAB-4 solution.Under blanket of nitrogen, the solution that obtains is joined in the toluene (150mL), and with mixture heated to 80 ℃.Under stirring fast, (24.72mL, 29.24g, toluene solution 0.316mol) (19mL) dropwise added in two hour time with EPI.After the adding, reactant was further heated 6 hours at 80 ℃, and cool to room temperature.Filter reaction mixture.The solid suspension collected in methanol (1L), was stirred 20 minutes, and filter.This methanol wash repeats twice.Solid suspension after filtering in 20% NaOH (1L) aqueous solution, was stirred 20 minutes, and filter.This NaOH solution washing of 20% repeats twice.Solid suspension after filtering in methanol (1L), was stirred 20 minutes, and filter.This methanol wash repeats once.Solid suspension after filtering in deionized water (2L), was stirred 20 minutes, and filter.This deionized water wash repeats twice.Polymer (weight in wet base is 51.81g) lyophilizing with after filtering obtains 26.61g.Expansion rate in the technical process is 0.947mL/g.

Embodiment 53

In 90 fens clock times, with spissated HCl (12.5mL) join DAB-4 (20g, 0.0632mol) in, it cools off in ice bath, keeps the temperature of DAB-4 solution to be lower than 10 ℃.In independent flask, DBSA, sodium chloride (3.69g) and deionized water (8.60g) are stirred, until whole dissolvings.DBSA and sodium chloride solution are joined in the DAB-4 solution.Under blanket of nitrogen, the solution that obtains is joined in the toluene (150mL), and with mixture heated to 80 ℃.Under stirring fast, (4.94mL, 5.84g, toluene solution 0.0632mol) (19mL) dropwise added in two hour time with EPI.After the adding, reactant was further heated 6 hours at 80 ℃, and cool to room temperature.Filter reaction mixture.The solid suspension collected in methanol (2L), was stirred 20 minutes, and filter.This methanol wash repeats twice.Solid suspension after filtering in 20% NaOH (2L) aqueous solution, was stirred 20 minutes, and filter.This NaOH solution washing of 20% repeats twice.Solid suspension after filtering in methanol (2L), was stirred 20 minutes, and filter.This methanol wash repeats once.Solid suspension after filtering in deionized water (4L), was stirred 20 minutes, and filter.This deionized water wash repeats twice.With polymer (weight in wet base the is 144.57g) lyophilizing after filtering.Freeze dried material being suspended in the deionized water, and adding spissated HCl in suspension, is 5 until pH.Lyophilizing obtains 20.38g.Expansion rate in the technical process is 6.09mL/g.

Embodiment 54

In 90 fens clock times, with spissated HCl (104.10g) join DAB-4 (167.2g, 0.528mol) in, it cools off in ice bath, keeps the temperature of DAB-4 solution to be lower than 10 ℃.In independent flask, DBSA, sodium chloride (30.8g) and deionized water (71.87g) are heated to 60 ℃, continue 20 minutes, until whole dissolvings.DBSA and sodium chloride solution are joined in the DAB-4 solution.Under blanket of nitrogen, the solution that obtains is joined in the toluene (1086g), and with mixture heated to 80 ℃.Under stirring fast, (103.25mL, 122.14g, toluene solution 1.32mol) (155mL) dropwise added in two hour time with EPI.After the adding, reactant was further heated 6 hours at 80 ℃, and cool to room temperature.Filter reaction mixture.The solid suspension collected in methanol (2L), was stirred 20 minutes, and filter.This methanol wash repeats twice.Solid suspension after filtering in 20% NaOH (2L) aqueous solution, was stirred 20 minutes, and filter.This NaOH solution washing of 20% repeats twice.Solid suspension after filtering in methanol (2L), was stirred 20 minutes, and filter.This methanol wash repeats once.Solid suspension after filtering in deionized water (4L), was stirred 20 minutes, and filter.This deionized water wash repeats twice.With the polymer (weight in wet base is 560.24g) after filtering, lyophilizing obtains 139.71g.Expansion rate in the technical process is 3.01mL/g.Analysis result: C, 59.77; H, 11.16; N, 17.67; Cl, 1.41; S,＜0.11.

Embodiment 55

At room temperature, in the agitating solution of DAB-4 (25g) and deionized water (16.14g), add EPI (2.92g).During the adding, reaction temperature is raised to 63 ℃.After finishing adding, solution is heated to 80 ℃, continues 18 hours.There is not colloid to form.Reactant is heated to 90 ℃, continues 2 hours, and cool to room temperature.There is not colloid to form.The EPI (15.40g) that in reaction, adds another part.Reaction temperature is raised to 74 ℃, and reaction forms colloid.Reactant is heated to 80 ℃, continues 18 hours, and be heated to 90 ℃, continue 2 hours.Behind the cool to room temperature, colloid is dispersed into small pieces, and is suspended in the deionized water of 4L, stir and filter.This washing repeats once.Colloid after filtering is suspended in once more in the deionized water of 4L and stirs (conductivity of suspension is 0.24mS/cm).Polymer (weight in wet base is 205.81g) after the washing is dry under 60 ℃ in forced air oven, obtain 27.01g.With dried polymer suspension in deionized water (3L) and stir 1 hour (pH of suspension is 9.7).Adding spissated HCl in this suspension, is 5 until pH, filters this suspension.The polymer (weight in wet base is 255.73g) of washing is dry under 60 ℃ in forced air oven, obtain 36.13g.Expansion rate in the technical process is 6.08mL/g.

Embodiment 56

The 20mL chloroformic solution of the 4-1-chloro-4-methyl-benzene (technical grade is 90%, buys from Aldrich) of 2.2g (13mmol) is joined the chloroform mixture of 500mL of Anhydrous potassium carbonate of 10g DAB-8,2.69g (19.5mmol) of stirring, continue 1 hour.At room temperature stir and spend the night filtering mixt.Collect filtrate, dry on potassium carbonate, and on rotary evaporator, concentrate, obtain the yellow oily product of 11.4g.

Embodiment 57

The DAB-8 (embodiment 56) of the 4-1-chloro-4-methyl-benzene modification of 11.4g is joined in the three-neck flask of 250mL.This flask is provided with overhead type agitator, 25mL addition funnel (addition funnel), thermocouple and pH analyzer.The deionized water that adds 34mL.Stir the mixture, and in ice bath, be cooled to 7 ℃.Dropwise adding 37% HCl by addition funnel, is 1 until pH, and temperature is remained between 7-15 ℃.Remove cooling bath then, and mixture is purified 20 minutes in nitrogen.Add 2,2 '-azo two (2-amidine propane) dihydrochloride (114mg) was with mixture reuse nitrogen purge 10 minutes.Flask is connected with nitrogen pipeline.Reactant mixture was stirred 4.5 hours down at 55 ℃.At room temperature allow mixture overnight.Observing colloid forms.Colloid is placed in the beaker of 2L, adds the deionized water of 1L, stirred 30 minutes.Most of colloid dissolving.With ice bath mixture is cooled to 10 ℃.Dropwise adding 50% aqueous solution of sodium hydroxide by addition funnel, is 10.1 until pH.Temperature remains between 10-20 ℃.Solution is concentrated into 400mL on rotary evaporator.Dialysing with deionized water, (retaining molecular weight: 3500), and lyophilizing obtains 11.0g to mixture.Freeze dried material suspends in the deionized water of 700mL, and mixture is stirred 30 minutes (pH of suspension is 10.0).Adding spissated HCl, is 7.5 until pH of suspension.Filtering suspension liquid, wet polymer (weight in wet base 107.2g) lyophilizing obtains 7.4g.

Embodiment 58

The DAB-8 (embodiment 56) of the 4-1-chloro-4-methyl-benzene modification of 30g is joined in the three-neck flask of 250mL.This flask is provided with overhead type agitator, 25mL addition funnel, thermocouple and pH analyzer.The deionized water that adds 90mL.Stir the mixture, and in ice bath, be cooled to 7 ℃.Dropwise adding spissated HCl by addition funnel, is 1 until pH, and temperature is remained between 7-15 ℃.Remove cooling bath then, mixture is purified 20 minutes in nitrogen.Add 2,2 '-azo two (2-amidine propane) dihydrochloride (300mg) was with mixture reuse nitrogen purge 10 minutes.Flask is connected with nitrogen pipeline.Reactant mixture was stirred 3 hours at 55 ℃.Detect NMR 1H.NMR shows that the vinyl proton disappears.With ice bath mixture is cooled to 10 ℃.Dropwise adding 50% aqueous solution of sodium hydroxide by addition funnel, is 10.5 until pH.Dialysing with deionized water, (retaining molecular weight: 3500), and lyophilizing obtains 17.56g to mixture.

Embodiment 59

To gather { N-(DAB-8) methyl styrene } (10.0g, embodiment 58) is placed in 3 mouthfuls of flasks that 100mL is provided with the overhead type agitator.The deionized water that adds 35mL.Mixture was stirred 2 hours, until polymer dissolution.The EPI that adds 0.77g (8.4mmol).Mixture was stirred 4 hours.Observing colloid after 2 hours forms.Colloid placed under the room temperature spend the night.Colloid is put in the beaker of 2L, adds the deionized water of 1.4L, stir 30 minutes (conductivity is 0.94mS/cm, and pH 9.1).Adding several spissated HCl, is 7.2 until pH.Filter colloid (weight in wet base is 152g).Colloid is placed forced air oven (60 ℃) dry 20 hours, obtain 7.1g.

Embodiment 60

Poly-{ N-(DAB-8) methyl styrene } (embodiment 58) of 7.2g are placed in 3 mouthfuls of flasks that 100mL is provided with the overhead type agitator.The deionized water that adds 25mL.Mixture was stirred 1.5 hours, until polymer dissolution.The EPI that adds 1.11g (12mmol).Mixture stirred 3.5 hours.1.5 observing colloid after hour forms.Mixture placed under the room temperature spend the night.Colloid is put in the beaker of 2L, adds the deionized water of 1.4L, mixture is stirred 30 minutes (conductivity is 0.87mS/cm, and pH 9.0).Adding several spissated HCl, is 7.7 until pH.Filter colloid (weight in wet base is 164g).Colloid is placed forced air oven (60 ℃) dry 20 hours, obtain 5.3g.

Embodiment 61

(technical grade is 90% with the 4-1-chloro-4-methyl-benzene of 1.51g (8.9mmol), buy from Aldrich) the 20mL chloroformic solution join the 120mL chloroform mixture of 15g (8.9mmol) DAB-16,2.53g (18.3mmol) Anhydrous potassium carbonate of stirring, continue 1 hour.After at room temperature stirring is spent the night, filtering mixt.Collect filtrate, dry on potassium carbonate, and on rotary evaporator, concentrate, obtain the yellow oily product of 16.3g.

Embodiment 62

The DAB-16 (15.5g, embodiment 61) of 4-1-chloro-4-methyl-benzene modification is joined in the three-neck flask of 250mL.This flask is provided with overhead type agitator, 25mL addition funnel, thermocouple and pH analyzer.The deionized water that adds 60mL.Stir the mixture, and in ice bath, be cooled to 7 ℃.Dropwise adding spissated HCl by addition funnel, is 1.2 until pH, and temperature remains between 7-15 ℃.Remove cooling bath then, and mixture is purified 15 minutes in nitrogen.Add 2,2 '-azo two (2-amidine propane) dihydrochloride (155mg), with mixture reuse nitrogen purge 15 minutes.Flask is connected with nitrogen pipeline.Reactant mixture was stirred 3.5 hours at 55 ℃.1H NMR shows that the vinyl proton disappears.Mixture returns to room temperature.With ice bath mixture is cooled to 10 ℃.Dropwise adding sodium hydroxide (50% aqueous solution) by addition funnel, is 10.5 until pH.Temperature is remained between 10-20 ℃.Solution concentrates (being less than 45g) on rotary evaporator.Adding EPI (1.43g, 15.5mmol).Mixture at room temperature stirred 1.5 hours, and 55 ℃ of restir 3.5 hours.Under 55 ℃, after 10 minutes, form colloid.Colloid placed under the room temperature spend the night.Colloid is placed in the beaker of 5L, adds the deionized water of 2.5L, stirred 30 minutes.Filter colloid, and be put back in the beaker, add the deionized water of 2.5L, stir 30 minutes (conductivity is 0.96mS/cm, and pH 8.6).Adding several spissated HCl, is 7.3 until pH.Filter colloid (weight in wet base is 207g) and lyophilizing, obtain 12.6g.

Embodiment 63

In refrigerative DAB-16 deionized water solution in ice-water bath, add spissated HCl (6.28g).The pH of solution is 7.This solution contains the DAB-16 that equivalent is 22.88% (w/w).

Embodiment 64

Adding spissated HCl (9.5mL) in the deionized water and stirring solution (40mL) of DAB-16 (10.33g), is 8.1 until the pH of solution.Lyophilizing obtains 11.9g.

Embodiment 65

The 30mL chloroformic solution of 4-1-chloro-4-methyl-benzene (28g, technical grade is 90%, buys from Aldrich) was joined in 4 hour time DAB-Am-4 (272mL), Anhydrous potassium carbonate (30.3g) and chloroform (1300mL) mixture of stirring.After at room temperature stirring is spent the night, filtering mixt.Filtrate is used borate buffer solution extracting twice (each 1.3L; Prepare borate buffer solution by mixing 115.7g boric acid, 37.44g NaOH and 2.6L deionized water, pH of buffer is 9.5).Merging aqueous layer, add NaOH (40% aqueous solution), is 12.4 until pH.With twice of chloroform (each 1.4L) extraction water solution layer.The chloroform extraction liquid that merges is dry on potassium carbonate, filters, and concentrates on rotary evaporator, obtains the yellow oily product of 38.1g.

Embodiment 66

Joining among the spissated HCl in deionized water (58.56g) solution of the DAB-Am-4 of 1-chloro-4-methyl-benzene modification (17g, embodiment 65), is 1.0 until pH value of solution.Place blanket of nitrogen to transfer solution, add 2 then, 2 '-azo two (2-amidine propane) dihydrochloride (170mg), solution is 55 ℃ of following heated overnight.Behind the cool to room temperature, adding sodium hydroxide (50% aqueous solution), is 11 until pH.Add epoxychloropropane (0.32g) when stirring.Form colloid in 35 minutes.After at room temperature solidifying 4 days, colloid is dispersed into small pieces, and is suspended in the deionized water (3L), stir and filter.Polymer suspension after filtering in deionized water (2.5L), is stirred and filters.Filtering polymer suspension stirs (conductivity is 400mS/cm, and pH 9.6) in deionized water (3L).Adding spissated HCl in the suspension that stirs, is 7.9 until pH, filtering suspension liquid.Filtering material (weight in wet base is 1228g) is dry under 60 ℃ in forced air oven, obtain 12.7g.

Embodiment 67

The 30mL chloroformic solution of 4-1-chloro-4-methyl-benzene (23.8g, technical grade is 90%, buys from Aldrich) was joined in 3 hour time DAB-Am-4 (177.6g), Anhydrous potassium carbonate (25.73g) and chloroform (1100mL) mixture of stirring.At room temperature stirred for 3 nights, then filtering mixt.Filtrate is concentrated into 650mL on rotary evaporator, and with borate buffer solution extracting twice (each 1.25L; Prepare borate buffer solution by mixing 105.18g boric acid, 34g NaOH and 2.5L deionized water).Merging aqueous layer, add NaOH (50% aqueous solution), is 12.4 until pH.With twice of chloroform (each 1.3L) extraction water solution layer.The chloroform extraction liquid that merges is dry on potassium carbonate, filter, and on rotary evaporator, concentrate, obtain 42.6g.

Embodiment 68

Adding spissated HCl in deionized water (50.5mL) solution of the DAB-Am-4 of refrigerative 1-chloro-4-methyl-benzene modification in ice-water bath (21.6g, embodiment 75), is 1.1 until pH value of solution.Solution is placed under the blanket of nitrogen, adds 2 then, 2 '-azo two (2-amidine propane) dihydrochloride (170mg), and with solution 55 ℃ the heating 3 hours.Behind the cool to room temperature, adding sodium hydroxide (50% aqueous solution), is 10.45 until the pH of solution.With deionized water (20mL) dilute solution.Solution is divided into 4 parts (32.65g).

Embodiment 69

In the part of this solution, at room temperature stir in (32.65g, embodiment 68) and add epoxychloropropane (0.173g).Form colloid in 29 minutes.At room temperature after the solidify overnight, colloidal suspension in deionized water (2L), is stirred and filtered.Polymer suspension after filtering in deionized water (1.7L), and is stirred (conductivity is 0.92mS/cm, and pH 9.1).Adding spissated HCl in suspension, is 8.2 until pH, filters and stirred suspension (weight in wet base is 127.45g).This material is dry under 60 ℃ in forced air oven, obtain 4.5g.

Embodiment 70

(32.65g, embodiment 68) at room temperature stirs and adds epoxychloropropane (0.346g) in the part of this solution.Form colloid in 28 minutes.At room temperature after the solidify overnight, colloidal suspension in deionized water (2L), is stirred and filtered.Polymer suspension after filtering in deionized water (1.7L), and is stirred (conductivity is 0.84mS/cm, and pH 9.1).Adding spissated HCl, is 8.3 until the pH of suspension, filters and stirred suspension (weight in wet base is 106.39g).This material is dry under 60 ℃ in forced air oven, obtain 4.6g.

Embodiment 71

(32.65g, embodiment 68) at room temperature stirs and adds epoxychloropropane (0.519g) in the part of this solution.Form colloid in 17 minutes.At room temperature after the solidify overnight, colloidal suspension in deionized water (2L), is stirred and filtered.Polymer suspension after filtering in deionized water (1.7L), and is stirred (conductivity is 0.63mS/cm, and pH 8.6).Adding spissated HCl, is 8.0 until the pH of suspension, filters and stirred suspension (weight in wet base is 117.1g).This material is dry under 60 ℃ in forced air oven, obtain 4.8g.

Embodiment 72

(32.65g, embodiment 68) at room temperature stirs and adds epoxychloropropane (0.692g) in the part of this solution.Form colloid in 15 minutes.At room temperature after the solidify overnight, colloidal suspension in deionized water (2L), is stirred and filtered.Polymer suspension after filtering in deionized water (1.7L), and is stirred (conductivity is 0.58mS/cm, and pH 8.5).Adding spissated HCl, is 7.8 until the pH of suspension, filters and stirred suspension (weight in wet base is 106.8g).This material is dry under 60 ℃ in forced air oven, obtain 4.9g.

Embodiment 73

The 30mL chloroformic solution of 4-1-chloro-4-methyl-benzene (19.28g, technical grade is 90%, buys from Aldrich) was joined in 3 hour time DAB-Am-4 (144g), Anhydrous potassium carbonate (20.8g) and chloroform (700mL) mixture of stirring.At room temperature stir and spend the night, and filtering mixt.Filtrate is used borate buffer solution extracting twice (each 700mL; Prepare borate buffer solution by mixing 62.5g boric acid, 8gNaOH and 1.4L deionized water).Merging aqueous layer, and add NaOH (50% aqueous solution), is 12.7 until pH.With twice of chloroform (each 1L) extraction water solution layer.The chloroform extraction liquid that merges is dry on potassium carbonate, filters, and concentrates on rotary evaporator, obtains the yellow oil of 31.8g.

Embodiment 74

To adding among the spissated HCl in deionized water (14mL) solution of the DAB-Am-4 of refrigerative 4-1-chloro-4-methyl-benzene modification in ice-water bath (10g, embodiment 73), be 1 until pH value of solution.Solution is placed under the blanket of nitrogen, adds N then, N '-ethylene diacrylamine (0.375g) and 2,2 '-azo two (2-amidine propane) dihydrochloride (100mg).Under blanket of nitrogen, this solution is joined in toluene (300mL) solution of polyvinyl acetate (10g) with syringe.Fiercely stir the mixture, and be heated to 65 ℃, continue 2 hours 20 minutes.Behind the cool to room temperature, filtering mixt.Filtering material is suspended in the methanol (800mL), stirs and filter.Material after filtering is suspended in the methanol (800mL), stirs and filter.Material after filtering is suspended in the deionized water (1.5L), and stirring (conductivity is 0.62mS/cm, and pH 3.6).Adding NaOH (50% aqueous solution) in suspension, is 7.2 until pH.Filter this material (weight in wet base is 228g) and in forced air oven, descend drying, obtain 11.9g at 60 ℃.

Embodiment 75

To gather (epoxychloropropane) (1.04g buys from Aldrich), DAP-Am-4 (10.72g) and 1-methyl-2-pyrrolidone alkane (80mL) solution 140 ℃ of heating 48 hours.Behind the cool to room temperature, reaction solution is poured in the ether, after the standing over night, from precipitation, pours out liquid level.Precipitation is dissolved in the deionized water, and dialyses with deionized water (film MWCO:3500).Dialysis solution is concentrated down at 60 ℃ in forced air oven, and lyophilizing obtains 1.45g.

Embodiment 76

The part of gathering (epoxychloropropane) (1.37g, embodiment 75) of DAP-Am-4 modification is suspended in the deionized water (12g), adds several NaOH (50% aqueous solution), and in the container of sealing, heat down in 60 ℃.Behind the cool to room temperature, mixture is diluted with deionized water (6g), and the pH of suspension is adjusted into 10.Solution is placed under the blanket of nitrogen, adds epoxychloropropane (30 μ L) then, at room temperature stir 4 hours after, add another part epoxychloropropane (30 μ L) again, stir under the room temperature and spend the night, add the 3rd part of epoxychloropropane (30 μ L).With mixture after 60 ℃ of heated overnight, cool to room temperature then, and being suspended in the deionized water (250mL).The pH of suspension is adjusted into 7.After at room temperature stirring 1 hour, with the deionized water mixture of dialysing.Dialysis solution is dry under 60 ℃ in forced air oven, obtain 1.35g.At 1 hour and 5 hours, external phosphate was in conjunction with being respectively 0.00 and 0.00mmol/g.

Embodiment 77

With the 20mL chloroformic solution of 4-1-chloro-4-methyl-benzene (0.405mL, technical grade is 90%, buys from Aldrich) during joining DAB-Am-8 (2g), Anhydrous potassium carbonate (0.538g) and chloroform (100mL) mixture of stirring in 55 minutes in the clock time.At room temperature stir and spend the night filtering mixt.Collect filtrate, and on rotary evaporator, concentrate, obtain 2.35g.

Embodiment 78

Slowly adding spissated HCl in deionized water (7mL) solution of DAB-Am-8 and 4-1-chloro-4-methyl-benzene (2.3g, embodiment 77) reaction, is 1.0 until the pH of solution.Solution is placed under the blanket of nitrogen, adds 2 then, 2 '-azo two (2-amidine propane) dihydrochloride (23mg), and with solution 55 ℃ of down heating 3 hours 40 minutes, then 60 ℃ of heating 2 hours.Behind the cool to room temperature, stir adding deionized water (150mL).Adding NaOH (50% aqueous solution), is 10.9 until the pH of solution.Mixture is dialysed with deionized water (film MWCO:3500) with deionized water (50mL) dilution, and lyophilizing obtains 1.04g.Adding deionized water (104mL) in freeze dried substance, and add spissated HCl, is 8.1 until pH.Filtering mixt, and the material after will filtering (weight in wet base is 12.8g) is dry under 60 ℃ in forced air oven, obtains 0.90g.At 1 hour and 5 hours, external phosphate was in conjunction with being respectively 0.51 and 0.19mmol/g.

Embodiment 79

The 30mL chloroformic solution of 4-1-chloro-4-methyl-benzene (0.248g, technical grade is 90%, buys from Aldrich) was joined in 1 hour time DAB-Am-16 (2.8g), Anhydrous potassium carbonate (0.338g) and chloroform (100mL) mixture of stirring.At room temperature stir and spend the night filtering mixt.Collect filtrate, and on rotary evaporator, concentrate, obtain 2.85g.

Embodiment 80

Slowly adding spissated HCl in deionized water (8.9mL) solution of DAB-Am-16 and 4-1-chloro-4-methyl-benzene (2.81g, embodiment 79) reaction, is 1.1 until pH value of solution.Under blanket of nitrogen, place solution, add 2 then, 2 '-azo two (2-amidine propane) dihydrochloride (28mg), and with solution 55 ℃ of down heating 3 hours.Behind the cool to room temperature, reactant mixture is dialysed with deionized water (film MWCO:3500), and lyophilizing obtains 2.78g.

Embodiment 81

Adding NaOH (50% aqueous solution) in the reactant mixture of refrigerative polymeric DAB-Am-16 and 4-1-chloro-4-methyl-benzene in ice-water bath (2.65g, embodiment 80) and in the deionized water (10mL), is 10.3 until pH.Add epoxychloropropane (0.0205g), mixture was at room temperature stirred 6 hours, then 60 ℃ of following heated overnight.Add another part epoxychloropropane (0.222g), and mixture was stirred 30 minutes, form until colloid.After at room temperature solidifying 16 hours, colloid is dispersed into small pieces, and is suspended in the deionized water (600mL), stirs and filters.Filtering material is suspended in the deionized water (600mL) and stirs (conductivity is 0.27mS/cm, and pH 8.5).Adding spissated HCl, is 7.7 until the pH of suspension.Filter and lyophilizing, obtain 1.56g.At 1 hour and 5 hours, external phosphate was in conjunction with being respectively 0.27 and 0.11mmol/g.

Embodiment 82

To gather (epoxychloropropane) (3.5g), DAP-Am-4 (27.23g) and 1-methyl-2-pyrrolidone alkane (240mL) solution is 140 ℃ of heating 48 hours.Behind the cool to room temperature, reaction solution is poured in the ether, after the standing over night, from precipitation, pours out liquid level.Precipitation is dissolved in deionized water, and dialyses with deionized water (film MWCO:3500).Dialysis solution concentrates down at 60 ℃ in forced air oven, and lyophilizing obtains 7.8g.The part of this material (7.5g) is suspended in the deionized water (60g), adds several NaOH (50% aqueous solution), and the sealing container in 60 ℃ of heating.Behind the cool to room temperature, mixture is diluted with deionized water, and the pH of suspension is adjusted into 10.Mixture stirred after 1 hour, filter, and in forced air oven 60 ℃ of following dried overnight.Deionized water is joined in the exsiccant material, and the pH of the suspension that stirs is adjusted to 7.Stir after 1 hour filtering mixt.Filtering material is suspended in the deionized water (1L), stirs 30 minutes, filters.Filtering material is dry under 60 ℃ in forced air oven, obtain 7.12g.At 1 hour and 5 hours, external phosphate was in conjunction with being respectively 0.00 and 0.00mmol/g.

The result: amine polymer minimizing urine phosphate (in the body-rat)

According to following method, the interior chelation data of body that following table provides rat urine phosphate to reduce.Listed embodiment sequence number refers to the above embodiments in the table.

Table 11

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	22.9	NA
Positive control	0.50	12.7	44.4	Negative control	0.50	22.9	NA
Positive control	0.50	12.7	44.4	12	0.50	8.0	65.1
13	0.50	7.7	66.4	12	0.50	8.0	65.1

Table 12.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	15.8	NA
Positive control	0.50	9.1	42.7	Negative control	0.50	15.8	NA
Positive control	0.50	9.1	42.7	41	0.50	8.3	47.7
49	0.50	8.9	43.5	41	0.50	8.3	47.7

Table 13.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	19.6	NA
Positive control	0.50	9.4	52.2	Negative control	0.50	19.6	NA
Positive control	0.50	9.4	52.2	15	0.50	7.1	63.7
40	0.50	17.5	10.7	15	0.50	7.1	63.7
40	0.50	17.5	10.7	42	0.50	7.2	63.2
44	0.50	6.1	69.0	42	0.50	7.2	63.2
44	0.50	6.1	69.0	44	0.35	11.6	41.2
44	0.25	11.0	44.2	44	0.35	11.6	41.2

Table 14.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	23.3	NA
Positive control	0.50	14.4	38.1	Negative control	0.50	23.3	NA
Positive control	0.50	14.4	38.1	Positive control	1.00	8.7	62.7
18	0.50	16.8	27.7	Positive control	1.00	8.7	62.7
18	0.50	16.8	27.7	19	0.50	16.2	30.5
22	0.50	13.2	43.1	19	0.50	16.2	30.5
22	0.50	13.2	43.1	23	0.50	14.2	39.0
24	0.50	11.2	51.9	23	0.50	14.2	39.0
24	0.50	11.2	51.9	25	0.50	11.3	51.3
31	0.50	8.8	62.4	25	0.50	11.3	51.3
31	0.50	8.8	62.4	59	0.50	15.6	67.1

Table 15.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	17.2	NA
Positive control	0.50	9.3	45.6	Negative control	0.50	17.2	NA
Positive control	0.50	9.3	45.6	20	0.50	6.2	63.8
21	0.50	7.5	56.4	20	0.50	6.2	63.8
21	0.50	7.5	56.4	31	0.50	6.9	59.9
32	0.50	10.9	36.6	31	0.50	6.9	59.9
32	0.50	10.9	36.6	61	0.50	8.9	48.4
62	0.50	9.8	43.1	61	0.50	8.9	48.4

Table 16.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	15.1	NA
Positive control	0.50	9.6	36.5	Negative control	0.50	15.1	NA
Positive control	0.50	9.6	36.5	7	0.50	13.1	13.0
10	0.50	14.5	3.8	7	0.50	13.1	13.0
10	0.50	14.5	3.8	56	0.50	10.8	28.6
69	0.49	8.6	42.7	56	0.50	10.8	28.6
69	0.49	8.6	42.7	70	0.50	10.8	28.4
71	0.50	9.9	34.6	70	0.50	10.8	28.4
71	0.50	9.9	34.6	72	0.50	8.4	44.7

Table 17.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	15.6	NA
Positive control	0.50	8.1	48.0	Negative control	0.50	15.6	NA
Positive control	0.50	8.1	48.0	74	0.50	11.8	24.7

Table 18.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	18.4	NA
Positive control	0.50	8.2	55.2	Negative control	0.50	18.4	NA
Positive control	0.50	8.2	55.2	54	0.50	15.9	13.5
55	0.50	11.1	39.5	54	0.50	15.9	13.5
55	0.50	11.1	39.5	56	0.50	7.3	60.5

Table 19.[high fat diet is to the bonded influence of phosphate]

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	13.4	NA
Positive control	0.25	8.0	40.5	Negative control	0.50	13.4	NA
Positive control	0.25	8.0	40.5	Positive control	0.50	6.7	50.2
Positive control	1.00	3.3	75.3	Positive control	0.50	6.7	50.2
Positive control	1.00	3.3	75.3	14	0.50	3.5	73.9
56	0.50	7.2	46.3	14	0.50	3.5	73.9

Table 20.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	20.0	NA
Positive control	0.50	12.1	39.4	Negative control	0.50	20.0	NA
Positive control	0.50	12.1	39.4	16	0.50	9.6	51.9
16	0.25	15.8	21.2	16	0.50	9.6	51.9
16	0.25	15.8	21.2	17	0.50	9.6	51.8
17	0.25	12.4	37.9	17	0.50	9.6	51.8
17	0.25	12.4	37.9	43	0.50	11.0	45.2
56	0.50	13.6	32.2	43	0.50	11.0	45.2

Table 21.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	15.3	NA
Positive control	0.50	8.2	46.8	Negative control	0.50	15.3	NA
Positive control	0.50	8.2	46.8	Positive control	1.0	4.0	73.6
26	0.50	4.3	71.9	Positive control	1.0	4.0	73.6

Table 22.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	23.1	NA
Positive control	0.50	9.7	58.0	Negative control	0.50	23.1	NA
Positive control	0.50	9.7	58.0	Positive control	1.0	5.5	76.3
26	0.50	7.7	66.6	Positive control	1.0	5.5	76.3
26	0.50	7.7	66.6	53	0.50	9.0	61

Table 23.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	15.9	NA
Positive control	0.50	8.9	44.3	Negative control	0.50	15.9	NA
Positive control	0.50	8.9	44.3	3	0.5	8.3	47.7

Table 24.

The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
The embodiment sequence number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	13.0	NA
Positive control	0.50	6.6	48.9	Negative control	0.50	13.0	NA
Positive control	0.50	6.6	48.9	66	0.50	5.7	55.8

Table 25.

Test number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
Test number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	15.1	NA
Positive control	0.50	8.5	43.3	Negative control	0.50	15.1	NA
Positive control	0.50	8.5	43.3	9	0.50	12.4	17.6

Table 26.

Test number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
Test number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	14.3	NA
Positive control	0.50	7.5	47.2	Negative control	0.50	14.3	NA
Positive control	0.50	7.5	47.2	2	0.50	10.9	24.0

Table 27.

Test number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
Test number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	17.7	NA
Positive control	0.50	7.8	55.9	Negative control	0.50	17.7	NA
Positive control	0.50	7.8	55.9	1	0.50	9.6	45.6

Table 28.

Test number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus
Test number	Dose of polymer (accounting for feedstuff weight %)	Phosphorus in the urine (mg/ days)	The minimizing % of urine phosphorus	Negative control	0.50	19.5	NA
Positive control	0.50	12.6	35.2	Negative control	0.50	19.5	NA
Positive control	0.50	12.6	35.2	63	(2.2 equaling 0.5% DAB-Am-16)	18.2	6.3

Method

Amine polymer is to urinating phosphatic minimizing (body in-rat)

Domestic male Sprague Dawley rat (SD) is used for test.Rat is placed on separately in the net bottom cage, feeds, and before test is used, make it adapt to 5 days at least with Purina 5002 diet.

In order to set up phosphorus secretion baseline, rat was placed the metabolic determination cage 48 hours.Collect their urine, and with Hitachi's analyser analysis phosphorus content wherein, to measure phosphorus secretion (mg/ days).Any rat that gets rid of exceptional value; Remaining rat is dispersed in each group.

Purina 5002 is as standard diet.The polymer of test is mixed with Purina 5002, is to account for 0.25%, 0.35%, 0.5% and 1% of feedstuff weight to obtain final concentration.The cellulose that accounts for weight 0.5% is as negative control.Sevelamer is as positive control.If use the diet (as table 19) of high fat content, to rat feeding feedstuff, it contains Purina 5002, accounts for the polymer of feedstuff weight 0.25%, 0.35%, 0.5% and 1%, and the refining olive oil that accounts for feedstuff weight 10%, wherein said olive oil is buied from Sigma commerce.For every rat, prepare the feedstuff of 200g.

Every rat is weighed, and use standard diet.After 4 days, standard feed replaces with therapeutic agent or high fat diet (or control diet of matched group).In the 5th day and the 6th day, from rat, collect urine samples and analysis every 24 hours (± 30 minutes).Weigh once more and test rat, calculate any weight increase or minimizing.Any remaining feedstuff of also weighing is to calculate the feedstuff that consume every day.With the phosphorus excretory variation of Excel program calculating with respect to baseline and cellulose negative control.The comparison that derives from the urine phosphorus content of testing rat is shown in table 11-28.The percentage ratio that urine phosphorus reduces in the research calculates with following equation:

Urine phosphorus reduces %=[(negative control urine phosphorus (mg/ days)-test urine phosphorus (mg/ days))/negative control urine phosphorus (mg/ days)] * 100

External phosphatic combination (mmol/g)

Behind drying loss, adjust the polymer weight of each sample, two samples of each polymer are weighed in plastic bottle.Preparation contains 10mM KH ₂PO ₄, 100mM N, the phosphate buffer of the 10mM of the oleic acid (NaOH with 1N adjusts to 7.0 with pH) of the glycochenodeoxycholate (GCDC) of NaCl, the 15mM of N-two [2-ethoxy]-2-ammonia ethane sulfonic acid, 80mM and 15mM, and fully mixing.The phosphate buffer equal portions of 10mM are put into two sample bottles respectively.Solution is fully mixed, be placed into then in the swinging agitator, kept 1 hour down at 37 ℃.From solution, remove each etc. before the duplicate samples, put into polymer.Adopt disposable syringe and syringe filter that the sample equal portions are filled in the bottle.Filtering sample dilutes by 1 to 10 with deionized water (DI).Further sustained oscillation 4 hours (totally 5 hours), the repeated sampling process.Phosphate standard stock solution with 10mM prepares the phosphate standard, suitably after the dilution, obtains the standard of 0.3 to 1.0mM scope.With ion chromatography standard and sample.Draw standard curve, calculate each test solution not in conjunction with phosphate (mM).Phosphate with following equation calculations incorporated:

Bonded phosphate (mmol/g)=[(the unconjugated PO of 10- ₄) * Vol. * 1000]/MassP; Wherein:

The volume of Vol.=test solution (L); The quality (mg) of the polymer that MassP=LOD adjusts

Expansion rate in the technical process (mL/g)

Measure the expansion rate (SR) in the technical process of many embodiment with following equation:

The weight (g) of SR=(weight (g) of wet colloidal weight (g)-dry polymeric)/dry polymeric.

Shown in the present and what describe only is the preferred embodiments of the invention, to those skilled in the art, these embodiments only provide exemplary approach.Come for those skilled in the art, various changes, change with alternative and all do not deviate from content of the present invention.Should be appreciated that in implementing process of the present invention, can adopt the various variations of embodiment of the present invention.Should be clear and definite, claim of the present invention defines scope of the present invention, and these claim scopes in method and structure and equivalent all within the scope of the present invention.

Claims

1. pharmaceutical composition, it comprises at least a polymer, and described polymer contains at least a aminated compounds or its residue, and wherein said aminated compounds is as shown in the formula shown in the I:

Formula I

Wherein:

R represents independently:

R ₁Expression independently:

R ₂Expression independently:

R _AExpression independently:

Wherein, m represents 1 to 20 integer independently; N and s represent the integer of 1-20 independently; Q and r represent the integer of 0-2 independently; And R ' represents hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted aryl independently; Or R ' and contiguous R ' one or morely being connected of representing to comprise the cross-linking agent residue together, replacement or unsubstituted alicyclic group, replacement or unsubstituted aromatic group or replacement or unsubstituted heterocyclic group; Or being connected of R ' expression and another chemical compound;

Cross-linking agent or its residue;

And pharmaceutically acceptable excipient.

2. the compositions of claim 1, wherein said cross-linking agent or its residue contain epoxychloropropane or its residue.

3. the compositions of claim 1, wherein said cross-linking agent or its residue are epoxychloropropane or its residue.

4. the compositions of claim 1, r wherein is 0.

5. the compositions of claim 1, r wherein be 2 and q be 0.

6. the compositions of claim 1, r wherein be 2 and q be 2.

7. the compositions of claim 1, wherein said polymer is crosslinked.

8. the compositions of claim 1, wherein said another chemical compound contains described cross-linking agent or its residue, or contains other and connect chemical compound or its residue, and wherein said other connects chemical compound and contains the amine reactive group.

9. the compositions of claim 1, wherein said polymer is in conjunction with phosphate.

10. the compositions of claim 9, wherein said polymer comes in conjunction with phosphate with the amount greater than the 0.5mmol/g polymer.

11. the compositions of claim 1, m wherein is 3-6, and q is 0.

12. the compositions of claim 1, the expansion rate of wherein said chemical compound is less than 10.

13. the compositions of claim 1, wherein said aminated compounds comprises 1,4-two [two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] butane or its residue.

14. the compositions of claim 1, wherein said aminated compounds comprises 1,4-two [two [3-[two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] propyl group] amino] butane or its residue.

15. the compositions of claim 1, wherein said aminated compounds comprises 1,4-two [two [3-[two [3-[two [3-[two [3-[two (3-aminopropyl) amino] propyl group] amino] propyl group] amino] propyl group] amino] propyl group] amino] butane or its residue.

16. be used for the treatment of tetany, the renal insufficiency that kidney is synthetic, hypocalcemia causes of hyperphosphatemia, hypocalcemia, hyperparathyroidism, repressed calcitriol, the cartilaginous tissue heterotopic calcification that comprises joint, lung, kidney, conjunctiva and cardiac muscular tissue's calcification, the method of chronic nephropathy, ESRD and dialysis patient, described method comprises the polymer to patient's administering therapeutic effective dose that needs are arranged, this polymer comprises at least a aminated compounds or its residue, and wherein said aminated compounds is as shown in the formula shown in the I:

Formula I

Wherein:

R represents independently:

R ₁Expression independently:

R ₂Expression independently:

R _AExpression independently:

Wherein m represents 1 to 20 integer independently; N and s represent the integer of 1-20 independently; Q and r represent the integer of 0-2 independently; And R ' represents hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted aryl independently; Or R ' and contiguous R ' one or morely being connected of representing to comprise the cross-linking agent residue together, replacement or unsubstituted alicyclic group, replacement or unsubstituted aromatic group or replacement or unsubstituted heterocyclic group; Or being connected of R ' expression and another chemical compound;

Cross-linking agent or its residue;

And pharmaceutically acceptable excipient.

17. comprise the polymer of at least a aminated compounds or its residue, wherein said aminated compounds is as shown in the formula shown in the I:

Formula I

Wherein:

R represents independently:

R ₁Expression independently:

R ₂Expression independently:

R _AExpression independently:

Wherein m represents 1 to 20 integer independently; N and s represent the integer of 1-20 independently; Q and r represent the integer of 0-2 independently; And R ' represents hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted aryl independently; Or R ' and contiguous R ' one or morely being connected of representing to comprise the cross-linking agent residue together, replacement or unsubstituted alicyclic group, replacement or unsubstituted aromatic group or replacement or unsubstituted heterocyclic group; Or being connected of R ' expression and another chemical compound; And

Cross-linking agent or its residue.

18. comprise the polymer of at least a aminated compounds or its residue, wherein said aminated compounds is as shown in the formula shown in the I:

Formula I

Wherein:

R represents independently:

R ₁Expression independently:

R ₂Expression independently:

R _AExpression independently:

Wherein m represents 1 to 20 integer independently; N and s represent the integer of 1-20 independently; Q and r represent the integer of 0-2 independently; And R ' represents hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted aryl independently; Or or R ' and contiguous R ' one or morely being connected of representing to comprise the cross-linking agent residue together, replacement or unsubstituted alicyclic group, replacement or unsubstituted aromatic group or replacement or unsubstituted heterocyclic group; Or being connected of R ' expression and another chemical compound; And

Polymerisable group or its residue.

19. the polymer of claim 18, at least a portion of wherein said aminated compounds or its residue are the side group on the polymer.

20. the polymer of claim 18, wherein said polymer is crosslinked, or forms net.