Crosslinked polyvinylamine, polyallylamine, and polyethyleneimine for use as bile acid sequestrants

1. A crosslinked amine polymer comprising repeat units derived from reaction of a crosslinking agent and an amine repeat unit, the amine repeat unit being either an allyl amine repeat unit of formula 14 or a polyethyleneimine repeat unit of formula 15, wherein the repeat units of formulae 14 and 15 have the structures:

wherein n is an integer, and the crosslinking agent is X—R 1 —X or epihalohydrin wherein R 1 is independently C 8 to C 50 alkylene, each X is independently a leaving group, and a portion of the nitrogen atoms of the crosslinked amine polymer are substituted with a ligand selected from 2-(protected amino)-m-(heterocyclo)-1-oxoC m alkyl, 2-(protected amino)-1-oxoC m alkyl, 2-(protected amino)-3-methyl-1-oxoC m alkyl, 2-(protected amino)-4-methyl-1-oxoC m alkyl, 2-(protected amino)-1-oxo-m-arylC m alkyl, 2-(protected amino)-m-(alkylthio)-1-oxoC m alkyl, 2-(protected amino)-m-(aryl)-1-oxoC m alkyl, 2-(protected amino)-m-carboxy-1-oxoC m alkyl, 2-(protected amino)-m-guanidino-1-oxoC m alkyl, 2-(protected amino)-(m-1)-hydroxy-1-oxoC m alkyl, 2-(protected amino)-m-hydroxy-1-oxoC m alkyl, 2-(protected amino)-m-mercapto-1-oxoC m alkyl, m-(alkylamino)-m-oxoC m alkyl, m-(alkylheterocyclo)C m alkyl, m-amino-2-(protected amino)-1-oxoC m alkyl, m-amino-2-(protected amino)-1,m-dioxoC m alkyl, m-(x-aminoC x alkyl)heterocycloC m alkyl, (m-1)-amino-m-(heterocyclo)-1-oxoC m alkyl, m-(arylalkylamino)-m-oxoC m alkyl, m-(x-(alkylthio)C x alkylamino)-m-oxoC m alkyl, m-(x-aminoC x alkylamino)-m-oxoC m alkyl, m-(x-amino-x-oxoC x alkylamino)-m-oxoC m alkyl, m-(x-carboxyC x alkylamino)-m-oxoC m alkyl, m-(heterocycloalkylamino)-m-oxoC m alkyl, m-(x-hydroxyC x alkylamino)-m-oxoC m alkyl, m-((x-1)-hydroxyC x alkylamino)-m-oxoC m alkyl, m-(x-mercaptoC x alkylamino)-m-oxoC m alkyl, m-(x-trialkylammonioC x alkyl)heterocycloC m alkyl, m-(x-(2-(alkoxy)benzamido)C x alkylamino)-m-oxoC m alkyl, m-(x-(3-(alkoxy)benzamido)C x alkylamino)-m-oxoC m alkyl, m-(x-(4-(alkoxy)benzamido)C x alkylamino)-m-oxoC m alkyl, heterocycloalkyl selected from m-(1-methylpyrrolidinium-1-yl)C m alkyl, m-(2-(1H-indol-3-yl)ethylamino)-m-oxoC m alkyl, m-(2-methylthiazol-3-ium-3-yl)C m alkyl, m-(benzo[d]thiazol-3-ium-3-yl)C m alkyl, m-(pyridinium-1-yl)C m alkyl, m-(tetrahydro-1H-thiophenium-1-yl)C m alkyl, z-(1,2-dialkyl-1H-imidazol-3-ium-3-yl)C z alkyl, m-(2,3-dialkyl-1H-imidazol-3-ium-1-yl)C m alkyl, z-(1-alkyl-1H-imidazol-3-ium-3-yl)C z alkyl, m-(3-alkyl-1H-imidazol-3-ium-1-yl)C m alkyl, or z-(thiazol-3-ium-3-yl)C z alkyl; 2-(protected amino)-m-(heterocyclo)-1-oxoC m alkyl selected from 2-(protected amino)-m-(1H-indol-3-yl)-1-oxoC m -alkyl or 2-(protected amino)-m-(1H-imidazol-4-yl)-1-oxoC m alkyl; 2-(protected amino)-1-oxo-m-phenylC m alkyl; 2-(protected amino)-m-(hydroxyphenyl)-1-oxoC m alkyl; m-(alkylheterocyclo)C m alkyl selected from m-(3-alkyl-1H-imidazol-3-ium-1-yl)C m alkyl, m-(1-alkyl-1H-imidazol-3-ium-3-yl)C m alkyl, m-(1-alkyl-2-methyl-1H-imidazol-3-ium-3-yl)C m alkyl, or m-(3-alkyl-2-methyl-1H-imidazol-3-ium-1-yl)C m alkyl; m-(x-aminoC x alkyl)heterocycloC m alkyl selected from m-(3-(x-aminoC x alkyl)-1H-imidazol-3-ium-1-yl)C m alkyl or m-(1-(x-aminoC x alkyl)-1H-imidazol-3-ium-3-yl) C m alkyl; (m-1)-amino-m-(1H-indol-2-yl)-1-oxoC m alkyl; m-(arylalkylamino)-m-oxoC m alkyl selected from m-(hydroxyphenalkylamino)-m-oxoC m alkyl or m-(phenalkylamino)-m-oxo-C m alkyl; m-(x-(heterocyclo)C x alkyl)heterocycloC m alkyl selected from m-(1-(x-(1-methyl-1H-imidazol-3-ium-3-yl)C x alkyl)-1H-imidazol-3-ium-3-yl) C m alkyl, m-(1-(x-(3-methyl-1H-imidazol-3-ium-1-yl)C x alkyl)-1H-imidazol-3-ium-3-yl) C m alkyl, m-(3-(x-(1-methyl-1H-imidazol-3-ium-3-yl)C x alkyl)-1H-imidazol-3-ium-1-yl) C m alkyl, or m-(3-(x-(3-methyl-1H-imidazol-3-ium-1-yl)C x alkyl)-1H-imidazol-3-ium-1-yl) C m alkyl; m-(x-(1H-imidazol-4-yl)C x alkylamino)-m-oxoC m alkyl; or m-(x-trialkylammonioC x alkyl)heterocycloC m alkyl selected from m-(3-(x-trialkylammonio)C x alkyl)-1H-imidazol-3-ium-1-yl)C m alkyl or m-(1-(x-trialkylammonio)C x alkyl)-1H-imidazol-3-ium-3-yl)C m alkyl, a ligand of formula 6

*—R 46 —R 47 —R 48   (6)

or a combination thereof, wherein R 46 is C 6 to C 16 alkylene, R 47 is 1,y-bis(1-methylpiperidin-4-yl)C y alkylene, R 48 is C 6 to C 16 alkyl, m is an integer from 3 to 12, x is an integer from 1 to 12, y is an integer from 1 to 14, and z is an integer from 1 to 16.

2. The polymer of claim 1 wherein R 1 is a C 10 to C 14 alkylene.

3. The polymer of claim 1 herein the ligand has a molecular weight less than about 1600 Daltons.

4. The polymer of claim 3 wherein the ligand has a molecular weight less than about 800 Daltons.

5. The polymer of claim 1 , wherein the ligand is heterocycloalkyl selected from m-(1-methylpyrrolidinium-1-yl)C m alkyl, m-(2-(1H-indol-3-yl)ethylamino)-m-oxoC m alkyl, m-(2-methylthiazol-3-ium-3-yl)C m alkyl, m-(benzo[d]thiazol-3-ium-3-yl)C m alkyl, m-(pyridinium-1-yl)C m alkyl, m-(tetrahydro-1H-thiophenium-1-yl)C m alkyl, z-(1,2-dialkyl-1H-imidazol-3-ium-3-yl)C z alkyl, m-(2,3-dialkyl-1H-imidazol-3-ium-1-yl)C m alkyl, z-(1-alkyl-1H-imidazol-3-ium-3-yl)C z alkyl, m-(3-alkyl-1H-imidazol-3-ium-1-yl)C m alkyl, or z-(thiazol-3-ium-3-yl)C z alkyl; 2-(protected amino)-m-(heterocyclo)-1-oxoC m alkyl selected from 2-(protected amino)-m-(1H-indol-3-yl)-1-oxoC m -alkyl or 2-(protected amino)-m-(1H-imidazol-4-yl)-1-oxoC m alkyl; 2-(protected amino)-1-oxo-m-phenylC m alkyl; 2-(protected amino)-m-(hydroxyphenyl)-1-oxoC m alkyl; m-(alkylheterocyclo)C m alkyl selected from m-(3-alkyl-1H-imidazol-3-ium-1-yl)C m alkyl, m-(1-alkyl-1H-imidazol-3-ium-3-yl)C m alkyl, m-(1-alkyl-2-methyl-1H-imidazol-3-ium-3-yl)C m alkyl, or m-(3-alkyl-2-methyl-1H-imidazol-3-ium-1-yl)C m alkyl; m-(x-aminoC x alkyl)heterocycloC m alkyl selected from m-(3-(x-aminoC x alkyl)-1H-imidazol-3-ium-1-yl)C m alkyl or m-(1-(x-aminoC x alkyl)-1H-imidazol-3-ium-3-yl) C m alkyl; (m-1)-amino-m-(1H-indol-2-yl)-1-oxoC m alkyl; m-(arylalkylamino)-m-oxoC m alkyl selected from m-(hydroxyphenalkylamino)-m-oxoC m alkyl or m-(phenalkylamino)-m-oxo-C m alkyl; m-(x-(heterocyclo)C x alkyl)heterocycloC m alkyl selected from m-(1-(x-(1-methyl-1H-imidazol-3-ium-3-yl)C x alkyl)-1H-imidazol-3-ium-3-yl) C m alkyl, m-(1-(x-(3-methyl-1H-imidazol-3-ium-1-yl)C x alkyl)-1H-imidazol-3-ium-3-yl) C m alkyl, m-(3-(x-(1-methyl-1H-imidazol-3-ium-3-yl)C x alkyl)-1H-imidazol-3-ium-1-yl) C m alkyl, or m-(3-(x-(3-methyl-1H-imidazol-3-ium-1-yl)C x alkyl)-1H-imidazol-3-ium-1-yl) C m alkyl; m-(x-(1H-imidazol-4-yl)C x alkylamino)-m-oxoC m alkyl; or m-(x-trialkylammonioC x alkyl)heterocycloC m alkyl selected from m-(3-(x-trialkylammonio)C x alkyl)-1H-imidazol-3-ium-1-yl)C m alkyl or m-(1-(x-trialkylammonio)C x alkyl)-1H-imidazol-3-ium-3-yl)C m alkyl wherein m is an integer from 3 to 12, x is an integer from 1 to 12, and z is an integer from 1 to 16.

6. The polymer of claim 1 , wherein the ligand is 2-(protected amino)-m-(heterocyclo)-1-oxoC m alkyl, m-amino-2-(protected amino)-1,m-dioxoC m alkyl, m-amino-2-(protected amino)-1-oxoC m alkyl, 2-(protected amino)-1-oxoC m alkyl, 2-(protected amino)-m-(alkylthio)-1-oxoC m alkyl, 2-(protected amino)-m-(hydroxyphenyl)-1-oxoC m alkyl, 2-(protected amino)-1-oxo-m-phenylC m alkyl, 2-(protected amino)-m-(1H-imidazol-4-yl)-1-oxoC m alkyl, 2-(protected amino)-m-carboxy-1-oxoC m alkyl, 2-(protected amino)-3-methyl-1-oxoC m alkyl, 2-(protected amino)-4-methyl-1-oxoC m alkyl, 2-(protected amino)-m-mercapto-1-oxoC m alkyl, 2-(protected amino)-(m-1)-hydroxy-1-oxoC m alkyl, 2-(protected amino)-m-hydroxy-1-oxoC m alkyl, 2-(protected amino)-m-guanidino-1-oxoC m alkyl, m-(x-(alkylthio)C x alkylamino)-m-oxoC m alkyl, m-(hydroxyphenalkylamino)-m-oxoC m alkyl, m-oxo-m-(phenalkylamino)C m alkyl, m-(x-(1H-imidazol-4-yl)C x alkylamino)-m-oxoC m alkyl, m-(x-carboxyC x alkylamino)-m-oxoC m alkyl, m-(alkylamino)-m-oxoC m alkyl, m-(x-mercaptoC x alkylamino)-m-oxoC m alkyl, m-((x-1)-hydroxyC x alkylamino)-m-oxoC m alkyl, m-(x-hydroxyC x alkylamino)-m-oxoC m alkyl, m-(x-aminoC x alkylamino)-m-oxoC m alkyl, or m-(x-amino-x-oxoC x alkylamino)-m-oxoC m alkyl, wherein m is an integer from 3 to 12, and x is an integer from 1 to 12.

7. The polymer of claim 1 , wherein the ligand is of formula 6 and R 46 is C 8 to C 12 alkylene, R 47 is 1,y-bis(1-methylpiperidin-4-yl)C y alkylene, R 48 is C 8 to C 12 alkyl, and y is an integer from 1 to 6.

8. The polymer of claim 1 , wherein the ligand is 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)-1-oxopropyl, 5-(2-(4-(nonyloxy)benzamido)ethylamino)-5-oxopentyl, 10-(pyridinium-1-yl)decyl, 5-(2-(1H-indol-3-yl)ethylamino)-5-oxopentyl, 2-amino-3-(1H-indol-2-yl)-1-oxopropyl, 3-(1,2-dimethyl-1H-imidazol-3-ium-3-yl)propyl, 10-(1,2-dimethyl-1H-imidazol-3-ium-3-yl)decyl, 10-(1-methyl-1H-imidazol-3-ium-3-yl)decyl, 3-(thiazol-3-ium-3-yl)propyl, 3-(1-methylpyrrolidinium-1-yl)propyl, 3-(2-methylthiazol-3-ium-3-yl)propyl, 3-(benzo[d]thiazol-3-ium-3-yl)propyl, 3-(tetrahydro-1H-thiophenium-1-yl)propyl, 3-(3-methyl-1H-imidazol-3-ium-1-yl)propyl, 3-(1-methyl-1H-imidazol-3-ium-3-yl)propyl, 3-(3-(3-aminopropyl)-1H-imidazol-3-ium-1-yl)propyl, 3-(1-(3-aminopropyl)-1H-imidazol-3-ium-3-yl)propyl, 3-(3-(5-trimethylammonio)pentyl)-1H-imidazol-3-ium-1-yl)propyl, 3-(1-(5-trimethylammonio)pentyl)-1H-imidazol-3-ium-3-yl)propyl, 3-(3-decyl-1H-imidazol-3-ium-1-yl)propyl, 3-(1-decyl-1H-imidazol-3-ium-3-yl)propyl, 3-(3-(9-(3-methyl-1H-imidazol-3-ium-1-yl)nonyl)-1H-imidazol-3-ium-1-yl)propyl, 3-(1-(9-(1-methyl-1H-imidazol-3-ium-3-yl)nonyl)-1H-imidazol-3-ium-3-yl)propyl, 3-(1-(9-(3-methyl-1H-imidazol-3-ium-1-yl)nonyl)-1H-imidazol-3-ium-3-yl)propyl, 3-(3-(9-(1-methyl-1H-imidazol-3-ium-3-yl)nonyl)-1H-imidazol-3-ium-1-yl)propyl, 4-(3-decyl-1H-imidazol-3-ium-1-yl)butyl, 4-(1-decyl-1H-imidazol-3-ium-3-yl)butyl, 10-(1-decyl-2-methyl-1H-imidazol-3-ium-3-yl)decyl, 10-(3-decyl-2-methyl-1H-imidazol-3-ium-1-yl)decyl, 3-(1,2-dimethyl-1H-imidazol-3-ium-3-yl)propyl, 3-(2,3-dimethyl-1H-imidazol-3-ium-1-yl)propyl, 10-(2,3-dimethyl-1H-imidazol-3-ium-1-yl)decyl, 10-(1,2-dimethyl-1H-imidazol-3-ium-3-yl)decyl, 10-(1-methyl-1H-imidazol-3-ium-3-yl)decyl, 10-(3-methyl-1H-imidazol-3-ium-1-yl)decyl, 10-(1-butyl-1H-imidazol-3-ium-3-yl)decyl, 10-(3-butyl-1H-imidazol-3-ium-1-yl)decyl, 10-(1-methylpyrrolidinium-1-yl)decyl, 4-amino-2-(tert-butoxycarbonylamino)-1,4-dioxobutyl, 2-(tert-butoxycarbonylamino)-1-oxoethyl, 2-(tert-butoxycarbonylamino)-4-(methylthio)-1-oxobutyl, 5-(3-(methylthio)propylamino)-5-oxopentyl, 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)-1-oxopropyl, 5-(4-hydroxyphenethylamino)-5-oxopentyl, 2-(tert-butoxycarbonylamino)-1-oxo-3-phenylpropyl, 5-oxo-5-(phenethylamino)pentyl, 2-(tert-butoxycarbonylamino)-3-(1H-imidazol-4-yl)-1-oxopropyl, 5-(2-(1H-imidazol-4-yl)ethylamino)-5-oxopentyl, 2-(tert-butoxycarbonylamino)-3-carboxy-1-oxopropyl, 5-(2-carboxyethylamino)-5-oxopentyl, 2-(tert-butoxycarbonylamino)-3-methyl-1-oxobutyl, 5-(isobutylamino)-5-oxopentyl,(3R)-2-(tert-butoxycarbonylamino)-3-methyl-1-oxopentyl,(R)-5-(2-methylbutylamino)-5-oxopentyl, 2-(tert-butoxycarbonylamino)-3-mercapto-1-oxopropyl, 5-(2-mercaptoethylamino)-5-oxopentyl,(3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-1-oxobutyl,(R)-5-(2-hydroxypropylamino)-5-oxopentyl, 6-amino-2-(tert-butoxycarbonylamino)-1-oxohexyl, 5-(5-aminopentylamino)-5-oxopentyl, 5-amino-2-(tert-butoxycarbonylamino)-1,5-dioxopentyl, 5-(4-amino-4-oxobutylamino)-5-oxopentyl, 2-(tert-A butoxycarbonylamino)-5-guanidino-1-oxopentyl, 2-(tert-butoxycarbonylamino)-3-hydroxy-1-oxopropyl, 5-(2-hydroxyethylamino)-5-oxopentyl, 2-(tert-butoxycarbonylamino)-4-methyl-1-oxopentyl, 5-(isopentylamino)-5-oxopentyl, 2-(tert-butoxycarbonylamino)-4-carboxy-1-oxobutyl, 5-(3-carboxypropylamino)-5-oxopentyl, 2-(tert-butoxycarbonylamino)-1-oxopropyl, 5-(ethylamino)-5-oxopentyl, a ligand of formula 6

*—R 46 —R 47 —R 48   (6)

or a combination thereof, wherein R 46 is decylene, R 47 is 1,3-bis(1-methylpiperidin-4-yl)propane, and R 48 is decyl.

9. The polymer of claim 8 wherein the ligand is 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)-1-oxopropyl, 5-(2-(4-(nonyloxy)benzamido)ethylamino)-5-oxopentyl, 10-(pyridinium-1-yl)decyl, 5-(2-(1H-indol-3-yl)ethylamino)-5-oxopentyl, 2-amino-3-(1H-indol-2-yl)-1-oxopropyl, 3-(1,2-dimethyl-1H-imidazol-3-ium-3-yl)propyl, 10-(1,2-dimethyl-1H-imidazol-3-ium-3-yl)decyl, 10-(1-methyl-1H-imidazol-3-ium-3-yl)decyl, 3-(thiazol-3-ium-3-yl)propyl, 3-(1-methylpyrrolidinium-1-yl)propyl, 3-(2-methylthiazol-3-ium-3-yl)propyl, 3-(benzo[d]thiazol-3-ium-3-yl)propyl, 3-(tetrahydro-1H-thiophenium-1-yl)propyl, 3-(3-methyl-1H-imidazol-3-ium-1-yl)propyl, 3-(1-methyl-1H-imidazol-3-ium-3-yl)propyl, 3-(3-(3-aminopropyl)-1H-imidazol-3-ium-1-yl)propyl, 3-(1-(3-aminopropyl)-1H-imidazol-3-ium-3-yl)propyl, 3-(3-(5-trimethylammonio)pentyl)-1H-imidazol-3-ium-1-yl)propyl, 3-(1-(5-trimethylammonio)pentyl)-1H-imidazol-3-ium-3-yl)propyl, 3-(3-decyl-1H-imidazol-3-ium-1-yl)propyl, 3-(1-decyl-1H-imidazol-3-ium-3-yl)propyl, 3-(3-(9-(3-methyl-1H-imidazol-3-ium-1-yl)nonyl)-1H-imidazol-3-ium-1-yl)propyl, 3-(1-(9-(1-methyl-1H-imidazol-3-ium-3-yl)nonyl)-1H-imidazol-3-ium-3-yl)propyl, 3-(1-(9-(3-methyl-1H-imidazol-3-ium-1-yl)nonyl)-1H-imidazol-3-ium-3-yl)propyl, 3-(3-(9-(1-methyl-1H-imidazol-3-ium-3-yl)nonyl)-1H-imidazol-3-ium-1-yl)propyl, 4-(3-decyl-1H-imidazol-3-ium-1-yl)butyl, 4-(1-decyl-1H-imidazol-3-ium-3-yl)butyl, 10-(1-decyl-2-methyl-1H-imidazol-3-ium-3-yl)decyl, 10-(3-decyl-2-methyl-1H-imidazol-3-ium-1-yl)decyl, 3-(1,2-dimethyl-1H-imidazol-3-ium-3-yl)propyl, 3-(2,3-dimethyl-1H-imidazol-3-ium-1-yl)propyl, 10-(2,3-dimethyl-1H-imidazol-3-ium-1-yl)decyl, 10-(1,2-dimethyl-1H-imidazol-3-ium-3-yl)decyl, 10-(1-methyl-1H-imidazol-3-ium-3-yl)decyl, 10-(3-methyl-1H-imidazol-3-ium-1-yl)decyl, 10-(1-butyl-1H-imidazol-3-ium-3-yl)decyl, 10-(3-butyl-1H-imidazol-3-ium-1-yl)decyl, 10-(pyridinium-1-yl)decyl, 10-(1-methylpyrrolidinium-1-yl)decyl, a ligand of formula 6

*—R 46 —R 47 —R 48   (6)

or a combination thereof, wherein R 46 is decylene, R 47 is 1,3-bis(1-methylpiperidin-4-yl)propane, and R 48 is decyl.

10. The polymer of claim 9 , wherein the polymer has a swelling ratio of about 0.5 to about 10 grams of water per gram of polymer.

11. The polymer of claim 9 , wherein swelling ratio of the polymer is about 2 to about 5 grams of water per gram of polymer.

12. The polymer of claim 10 , wherein the polymer is a free flowing powder.

13. A pharmaceutical composition comprising the polymer of claim 1 and a pharmaceutically acceptable excipient.

14. A method of reducing serum LDL-cholesterol in an animal subject comprising administering an effective amount of a pharmaceutical composition of claim 13 to an animal subject in need thereof.

15. The crosslinked amine polymer of claim 1 wherein the amine repeat unit comprises an allyl amine repeat unit of formula 14:

16. The crosslinked amine polymer of claim 1 wherein the amine repeat unit comprises a polyethyleneimine repeat unit of formula 15: