US2017258825A1PendingUtilityA1
Amine polymers for use as bile acid sequestrants
Est. expiryFeb 24, 2030(~3.6 yrs left)· nominal 20-yr term from priority
Inventors:Eric ConnorKalpesh BiyaniScott HeckerInez LeesPaul ManskyYongqi MuFaleh SalaymehHongmin ZhangDavid E. BergbreiterGrace May HuynhMichael J. CopeElizabeth GokaAngela LeeDeidre MadsenJun ShaoXinnan Zhang
A61P 3/10A61P 3/06A61P 43/00A61P 3/00A61P 25/28A61P 13/00A61P 1/00A61P 17/04A61P 1/16C08G 73/0206A61K 45/06C08G 73/02A61K 31/785C08L 79/02C08G 73/0213A61K 31/13C08G 73/024C08G 73/0273C08G 73/0253C08G 73/0246A61K 48/0041C08G 73/028A61K 2300/00
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Claims
Abstract
The present invention provides crosslinked amine polymers effective for binding and removing bile salts from the gastrointestinal tract. These bile acid binding polymers or pharmaceutical compositions thereof can be administered to subjects to treat various conditions, including hypercholesteremia, diabetes, pruritus, irritable bowel syndrome-diarrhea (IBS-D), bile acid malabsorption, and the like.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An amine polymer comprising repeat units derived from polymerization of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer having two or three possible reaction sites, wherein the molar ratio of the amine monomer to the crosslinking monomer is in the range of from 1:3 to about 1:1.1, and the amine polymer has a binding affinity for bile acids of at least 0.46 mmol/g when measured using an in vitro A assay.
2 . An amine polymer comprising the reaction product of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer, wherein units of the polymer have the structure of formula 1
wherein
R 10 is derived from the crosslinking monomer and is C 2 to C 16 alkylene, —NH—C(NH)—NH—, —NH—C(NH 2 + )—NH—, or C 2 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy;
R 30 is derived from the amine monomer and is C 2 to C 12 alkylene, arylene, diformylheterocyclo, or C 2 to C 12 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, a cycloalkyl, an aryl, or a heterocyclo functional group;
each R 20 is independently C 2 to C 6 alkylene or C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group; and
at least one of R 10 or R 30 is a hydrophobic group having a calculated log P (c Log P) of greater than 4.
3 . An amine polymer comprising the reaction product of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer wherein units of the polymer have the structure of formula 1
wherein
R 10 is derived from the crosslinking monomer and is C 2 to C 16 alkylene, —NH—C(NH)—NH—, —NH—C(NH 2 + )—NH—, or C 2 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy;
R 30 is derived from the amine monomer and is C 2 to C 6 alkylene;
each R 20 is independently C 2 to C 6 alkylene or C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group; and
R 10 is a hydrophobic group having a calculated log P (c Log P) of greater than 4.
4 . An amine polymer comprising the reaction product of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer wherein units of the polymer have the structure of formula 1
wherein
R 10 is derived from the crosslinking monomer and is C 8 to C 16 alkylene, or C 8 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group;
R 30 is derived from the amine monomer and is C 2 to C 12 alkylene, arylene, diformylheterocyclo, or C 2 to C 12 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group; and
each R 20 is independently C 2 to C 6 alkylene or C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group.
5 . An amine polymer comprising the reaction product of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer wherein units of the polymer have the structure of formula 1
wherein
R 10 is derived from the crosslinking monomer and is C 2 to C 6 alkylene, or C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy;
R 30 is derived from the amine monomer and is C 8 to C 16 alkylene, arylene, diformylheterocyclo, or C 8 to C 16 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group; and
each R 20 is independently C 2 to C 6 alkylene or C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group.
6 . The amine polymer of any one of claims 2 to 5 wherein the polymer comprises primary and secondary amine atoms in a calculated ratio in the range of from 1:1 to about 1:5.
7 . The amine polymer of any one of claims 2 to 6 wherein the molar ratio of the amine monomer to the crosslinking monomer is in the range of from 1:3 to about 1:1.1.
8 . The amine polymer of any one of claims 2 to 7 having a binding affinity for bile acids of at least 0.46 mmol/g when measured using an in vitro A assay.
9 . An amine polymer comprising the reaction product of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer having two or three possible reaction sites,
said polymer being insoluble in water, at least some of said amine secondary nitrogen atoms being part of a crosslinked polymer network, the crosslinking monomer is a compound having the formula X-R 1 -X, wherein each X is independently a leaving group, and R 1 is C 8 to C 16 alkylene, or C 8 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, and the calculated log P (c Log P) of the crosslinking monomer is greater than 4.
10 . An amine polymer comprising the reaction product of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer having two or three possible reaction sites,
said polymer being insoluble in water, at least some of said amine secondary nitrogen atoms being part of a crosslinked polymer network, the amine monomer having at least one segment that is a C 8 to C 16 alkylene, arylene, or C 8 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, and a calculated log P (c Log P) of the at least one segment of the amine monomer is greater than 4, and the crosslinking monomer is a compound having the formula X-R 1 -X, wherein each X is independently a leaving group, and R 1 is C 2 to C 6 alkylene, or C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy.
11 . The polymer of claim 9 wherein the crosslinking monomer is X-R 1 -X wherein each X is independently a leaving group, and R 1 is C 8 to C 16 alkylene, or C 8 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with a heterocyclo functional group.
12 . The polymer of claim 10 wherein the crosslinking monomer is X-R 1 -X wherein each X is independently a leaving group, and R 1 is C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy.
13 . An amine polymer comprising repeat units derived from polymerization of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer having two or three possible reaction sites, wherein the molar ratio of the amine monomer to the crosslinking monomer is in the range of from 1:3 to about 1:1.1, and wherein:
said polymer binds phosphate in vitro in an amount of less than 0.3 mmol/gram of polymer when measured using a B assay; and said polymer binds bile acids with an in vitro capacity of greater than about 3 mmol/gram of polymer when measured using a B assay.
14 . An amine polymer comprising units of the polymer having nodes of positive charge separated by aliphatic segments, wherein the nodes of positive charge have a charge density of at least 19.0 mEq/g and a molecular weight of at least 200.0 g/mol and at least one aliphatic segment is bonded to each node of positive charge, the at least one aliphatic segment having a calculated log P (c Log P) greater than 4 and wherein each of the nodes of positive charge does not contain an aliphatic segment having a calculated log P (c Log P) greater than 4.
15 . An amine polymer comprising units of the polymer having nodes of positive charge separated by aliphatic segments, wherein the nodes of positive charge have a charge density greater than 17.3 mEq/g and the structure of formula A
wherein each R 20 is independently C 3 to C 8 alkylene or C 3 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group;
and wherein at least one aliphatic segment is bonded to each node of positive charge, each aliphatic segment having a calculated log P (c Log P) greater than 4.
16 . The amine polymer of claim 14 or 15 , wherein the at least one aliphatic segment is a C 8 to C 16 alkylene, or C 8 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group.
17 . The amine polymer of any one of claims 14 to 16 , wherein said polymer binds phosphate in vitro in an amount of less than 0.3 mmol/gram of polymer when measured using a B assay; and said polymer binds bile acids with an in vitro capacity of greater than about 3 mmol/gram of polymer when measured using the B assay.
18 . The amine polymer of claim 17 , wherein said polymer binds phosphate in vitro in an amount of less than 0.2 mmol/gram of polymer when measured using the B assay.
19 . The amine polymer of any one of claims 15 to 18 wherein each of the nodes of positive charge does not contain an aliphatic segment having a calculated log P (c Log P) greater than 4.
20 . An amine polymer comprising units of the polymer having the structure of formula 1
wherein
R 10 is C 2 to C 16 alkylene, arylene, —NH—C(NH)—NH—, —NH—C(NH 2 + )—NH—, dimethylbiphenyl, or C 2 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, a cycloalkyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy;
R 30 is C 2 to C 12 alkylene, arylene, diformylheterocyclo, or C 2 to C 12 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group; and
each R 20 is independently C 2 to C 8 alkylene or C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group;
said polymer binds phosphate in vitro in an amount of less than 0.3 mmol/gram of polymer when measured using a B assay; and
said polymer binds bile acids with an in vitro capacity of greater than about 3 mmol/gram of polymer when measured using a B assay.
21 . The amine polymer of claim 20 wherein the amine polymer comprises the reaction product of an amine monomer having six, seven or eight possible reaction sites and a crosslinking monomer and R 10 is derived from the crosslinking monomer and R 30 is derived from the amine monomer.
22 . The amine polymer of claim 20 wherein the amine polymer binds phosphate in vitro in an amount of less than 0.2 mmol/gram of polymer when measured using a B assay.
23 . The amine polymer of any of claims 1 to 22 wherein the calculated Log P is greater than 4.5.
24 . The amine polymer of any of claims 1 to 22 wherein the calculated Log P is greater than 5.
25 . The amine polymer of any of claims 1 to 22 wherein the calculated Log P is greater than 5.5.
26 . The amine polymer of any of claims 1 to 22 wherein the calculated Log P is greater than 6.
27 . An amine polymer comprising repeat units derived from polymerization of an amine monomer and a crosslinking monomer, wherein the amine monomer is an amine of formula 2 having the structure:
wherein each R 2 is independently C 2 to C 8 alkylene or C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with at least one amide functional group, and R 3 is C 2 to C 12 alkylene, arylene, diformylheterocyclo, or C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group; and
the crosslinking monomer is guanidine, a guanidinium salt, a compound having the formula X-R 1 -X, or a combination thereof, wherein each X is independently a leaving group, R 1 is C 8 to C 16 alkylene, or C 5 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy.
28 . The amine polymer of any one of claims 1 to 26 wherein the amine monomer is an amine of formula 2 having the structure:
wherein each R 2 is independently C 2 to C 8 alkylene or C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group, and R 3 is C 2 to C 12 alkylene, arylene, diformylheterocyclo, or C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group.
29 . The amine polymer of any one of claims 1 to 26 wherein the amine monomer is an amine of formula 2 having the structure:
wherein each R 2 is independently C 2 to C 8 alkylene or C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group, and R 3 is C 8 to C 16 alkylene, arylene, diformylheterocyclo, or C 8 to C 16 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group;
and the crosslinking monomer is a compound having the formula X-R 1 -X, wherein each X is independently a leaving group, R 1 is C 2 to C 6 alkylene or C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy.
30 . The amine polymer of claim 28 wherein the crosslinking monomer is guanidine, a guanidinium salt, a compound having the formula X-R 1 -X, or a combination thereof, wherein each X is independently a leaving group, R 1 is C 8 to C 16 alkylene, dimethylbiphenyl, or C 2 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with one or two phenyl, piperidinium or imidazolium functional groups.
31 . The amine polymer of claim 30 wherein the C 2 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with one or two phenyl, piperidinium or imidazolium functional groups is p-xylene, 1,3-bis(m-haloC m alkyl)-1H-imidazol-3-ium, 4,4′-(C x alkane-Lx-diyl)bis(1-(m-haloC m alkyl)-1-methylpiperidinium), or 1-(q-haloC q alkyl)-3-(m-(3-(p-haloC p alkyl)-1H-imidazol-3-ium-1-yl)C m alkyl)-1H-imidazol-3-ium, wherein m is an integer from 2 to 14, p is an integer from 2 to 14, q is an integer from 2 to 14, and x is an integer from 2 to 8.
32 . The amine polymer of claim 28 wherein the crosslinking monomer is guanidine, a compound having the formula X-R 1 -X wherein R 1 is C 8 to C 16 alkylene, or a combination thereof, and the amine polymer comprises a comonomer, the comonomer being C m alkane-1,m-diyldiamine, alkylenedicycloalkanamine, (m-aminoC m alkyl)heterocycle, 3-(m-aminoC m alkyl)-1H-imidazol-3-ium, or a combination thereof, wherein m is an integer from 2 to 16, and each X is independently a leaving group.
33 . The amine polymer of claim 29 wherein the crosslinking monomer is a compound having the formula X-R 1 -X wherein R 1 is C 2 to C 6 alkylene, and the amine polymer comprises a comonomer, the comonomer being C m alkane-1,m-diyldiamine, alkylenedicycloalkanamine, (m-aminoC m alkyl)heterocycle, 3-(m-aminoC m alkyl)-1H-imidazol-3-ium, or a combination thereof, wherein m is an integer from 2 to 16, and each X is independently a leaving group.
34 . The amine polymer of claim 29 wherein R 3 is octylene, decylene, undecylene, or dodecylene.
35 . The amine polymer of claim 29 wherein the polymer comprises a comonomer, the comonomer being hexane-1,6-diyldiamine, heptane-1,7-diylamine, octane-1,8-diyldiamine, nonane-1,9-diylamine, decane-1,10-diyldiamine, undecane-1,11-diylamine, dodecane-1,12-diyldiamine, 4,4′-methylenedicyclohexanamine, 3-(3-aminopropyl)-1H-imidazol-3-ium, or a combination thereof.
36 . The amine polymer of claim 28 wherein R 3 is ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, decylene, undecylene, dodecylene, 1,4-phenylenedimethyl, 1,6-dioxohexane-1,6-diyl, 1,4-dioxobutane-1,4-diyl or 2,6-diformylpyridine.
37 . The amine polymer of claim 1 wherein the amine monomer is an amine of formula 3 having the structure:
wherein each R 21 is independently C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with at least one sulfur atom, and R 31 is C 2 to C 12 alkylene, arylene, diformylheterocyclo, or C 2 to C 12 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group; and
the crosslinking monomer is guanidine, a guanidinium salt, a compound having the formula X-R 1 -X, or a combination thereof, wherein each X is independently a leaving group, and R 1 is C 2 to C 16 alkylene, arylene, dimethylbiphenyl, or C 2 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy.
38 . The amine polymer of claim 37 wherein each R 21 is m-sulfidoC m alkyl, m is an integer from 1 to 6 and R 31 is C 3 to C 8 alkylene.
39 . An amine polymer comprising repeat units derived from polymerization of an amine monomer of formula 2 and a crosslinking monomer, wherein the amine monomer of formula 2 has the structure:
wherein each R 2 is independently C 2 to C 8 alkylene or C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide functional group; and R 3 is C 2 to C 12 alkylene, arylene, diformylheterocyclo, or C 2 to C 12 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group; and a portion of the nitrogen atoms of the amine polymer are substituted with a ligand selected from aminoalkyl, aryl, arylalkyl, oxoalkyl, cycloalkyl, (cycloalkyl)alkyl, guanidino, heterocyclo, heterocycloalkyl, (trialkylammonio)alkyl, 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, a ligand of formula 4
*-R 46 -R 47 -R 48 (4)
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.
40 . The amine polymer of any one of claims 1 to 38 wherein a portion of the nitrogen atoms of the amine polymer are substituted with a ligand selected from alkyl, aminoalkyl, aryl, arylalkyl, oxoalkyl, cycloalkyl, (cycloalkyl)alkyl, guanidino, heterocyclo, heterocycloalkyl, (trialkylammonio)alkyl, 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, a ligand of formula 4
*-R 46 -R 47 -R 48 (4)
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.
41 . The amine polymer of claim 39 or 40 wherein the ligand is arylalkyl selected from naphthalen-2-ylalkyl or naphthalen-1-ylalkyl; 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.
42 . The amine polymer of claim 39 or 40 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.
43 . The amine polymer of claim 39 or 40 wherein the ligand is 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)-1-oxopropyl, 5-(2-(4-(nonyloxy)benzamido)ethylamino)-5-oxopentyl, (4,5-dihydro-1H-imidazolyl, 10-(pyridinium-1-yl)decyl, 2-(1H-indol-3-yl)ethyl, 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-aminopropyl, 3-cyclohexylpropyl, 3-phenylpropyl, 3-(trimethylammonio)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, naphthalen-2-ylmethyl, naphthalen-1-ylmethyl, 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-butoxycarbonylamino)-5-guanidino-1-oxopentyl, 5-(4-guanidinobutylamino)-5-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 4
*-R 46 -R 47 -R 48 (4)
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.
44 . The amine polymer of claim 39 or 40 wherein the ligand is 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)-1-oxopropyl, 5-(2-(4-(nonyloxy)benzamido)ethylamino)-5-oxopentyl, (4,5-dihydro-1H-imidazolyl, 10-(pyridinium-1-yl)decyl, 2-(1H-indol-3-yl)ethyl, 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-aminopropyl, 3-cyclohexylpropyl, 3-phenylpropyl, 3-(trimethylammonio)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, naphthalen-2-ylmethyl, naphthalen-1-ylmethyl, a ligand of formula 4
*-R 46 -R 47 -R 48 (4)
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.
45 . The amine polymer of any one of claims 39 to 42 wherein the protecting group is independently —C(O)OR 49 , —C(O)R 50 , wherein R 49 is alkyl or aryl, and R 50 is amino, hydrogen, alkyl, or haloalkyl.
46 . The amine polymer of claim 39 wherein the crosslinking monomer is guanidine, a guanidinium salt, a compound having the formula X-R 1 -X, or a combination thereof, wherein each X is independently a leaving group, and R 1 is C 2 to C 16 alkylene, arylene, dimethylbiphenyl, or C 2 to C 50 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group, or one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy.
47 . The amine polymer of any one of claims 39 to 46 comprising about 5 mole % to about 60 mole % ligand based on the moles of amine monomer.
48 . The amine polymer of any one of claims 39 to 46 comprising about 5 mole % to about 50 mole % ligand based on the moles of amine monomer.
49 . The amine polymer of any one of claims 39 to 46 comprising about 10 mole % to about 30 mole % ligand based on the moles of amine monomer.
50 . The amine polymer of any one of claims 9 to 12 , 27 , and 29 to 49 wherein X is halo, epoxy, diaziridino or a combination thereof.
51 . The amine polymer of any one of claims 29 to 50 wherein R 1 is C 8 to C 14 alkylene.
52 . The amine polymer of claim 51 wherein R 1 is decylene or dodecylene.
53 . The amine polymer of any one of claims 2 , 5 to 8 , 10 , 20 - 26 , 29 , 37 , 38 , 40 to 45 , and 47 to 50 wherein R 1 or R 10 is C 2 to C 6 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is substituted with hydroxy.
54 . The amine polymer of claim 53 wherein R 1 or R 10 is —CH 2 —CH(OH)—CH 2 —.
55 . The amine polymer of any one of claims 29 to 54 wherein R 3 or R 30 is C 3 to C 12 alkylene.
56 . The amine polymer of claim 55 wherein R 3 or R 30 is butylene.
57 . The amine polymer of claim 55 wherein R 3 or R 30 is decylene.
58 . The amine polymer of any one of claims 2 , 4 to 8 , 20 to 36 and 39 to 54 wherein R 3 or R 30 is dodecylene.
59 . The amine polymer of any one of claims 2 to 8 , 20 to 36 and 39 to 58 wherein each R 2 or R 20 is independently C 2 to C 6 alkylene.
60 . The amine polymer of claim 59 wherein each R 2 or R 20 is independently C 2 to C 4 alkylene.
61 . The amine polymer of claim 60 wherein each R 2 or R 20 is propylene.
62 . The amine polymer of any one of claims 1 to 61 having an in vivo binding capacity at least 25% greater than colesevelam hydrochloride when measured at a dosage of 0.5% in male Golden Syrian hamsters fed a Western diet.
63 . The amine polymer of claim 62 wherein the in vivo binding capacity is at least 50% greater than colesevelam hydrochloride.
64 . The amine polymer of claim 62 wherein the in vivo binding capacity is at least 75% greater than colesevelam hydrochloride.
65 . The amine polymer of claim 62 wherein the in vivo binding capacity is at least 100% greater than colesevelam hydrochloride.
66 . The amine polymer of any one of claims 1 to 65 wherein the binding affinity for bile acids is at least about 0.46 mmol/g when measured using an in vitro A assay.
67 . The amine polymer of any one of claims 1 to 65 wherein the binding affinity for bile acids is at least about 0.55 mmol/g when measured using an in vitro A assay.
68 . The amine polymer of any one of claims 1 to 65 wherein the binding affinity for bile acids is at least about 0.60 mmol/g when measured using an in vitro A assay.
69 . The amine polymer of any one of claims 1 to 65 wherein the binding affinity for bile acids is at least about 0.65 mmol/g when measured using an in vitro A assay.
70 . The amine polymer of any one of claims 1 to 69 having a binding capacity at least 25% greater than colesevelam hydrochloride when measured using an in vitro B assay.
71 . The amine polymer of claim 70 wherein the in vitro binding capacity is at least 50% greater than colesevelam hydrochloride when measured using an in vitro B assay.
72 . The amine polymer of claim 70 wherein the in vivo binding capacity is at least 75% greater than colesevelam hydrochloride when measured using an in vitro B assay.
73 . The amine polymer of claim 70 wherein the in vivo binding capacity is at least 100% greater than colesevelam hydrochloride when measured using an in vitro B assay.
74 . The amine polymer of any one of claims 1 to 73 , wherein, in an in vivo measurement, on average there are at least 11% primary bile acids in the feces.
75 . The amine polymer of any one of claims 1 to 73 , wherein, in an in vivo measurement, on average there are at least 15% primary bile acids in the feces.
76 . The amine polymer of any one of claims 1 to 75 wherein the binding capacity for bile acids is at least about 2.22 mmol/g when measured using the B assay.
77 . The amine polymer of any one of claims 1 to 76 wherein the concentration of bound taurocholic acid is greater than 1.5 mmol/g polymer and the concentration of unbound taurocholic acid is less than 1.0 mmol/g polymer when the polymer is placed in a buffer solution having a 2.5 mM taurocholic acid concentration at 37° C. and the concentration of bound taurocholic acid is greater than 5.0 mmol/g polymer and the concentration of unbound taurocholic acid is greater than 4.0 mmol/g polymer when the polymer is placed in a buffer solution having a taurocholic acid concentration of at least 10 mM at 37° C.
78 . The amine polymer of any one of claims 1 to 76 wherein the concentration of bound glycodeoxycholate is greater than 1.0 mmol/g polymer and the concentration of unbound glycodeoxycholate is less than 0.1 mmol/g polymer when the polymer is placed in a buffer solution having a 1.25 mM glycodeoxycholate concentration at 37° C. and the concentration of bound glycodeoxycholate is greater than 6.0 mmol/g polymer and the concentration of unbound glycodeoxycholate is greater than 2.0 mmol/g polymer when the polymer is placed in a buffer solution having a glycodeoxycholate concentration of at least 10 mM at 37° C.
79 . An amine polymer useful as a bile acid sequestrant, wherein, in a buffer solution at 37° C. containing less than 2.6 mM taurocholic acid, the amine polymer binds more of the acid than sevelamer and in a buffer solution at 37° C. containing more than 5.0 mM taurocholic acid the amine polymer binds more of the acid than colesevelam.
80 . The amine polymer of claim 79 having the structure of any one of claims 1 to 75 .
81 . The amine polymer of claim 80 wherein the amine polymer is derived from the polymerization of an amine monomer and a crosslinking monomer wherein the amine monomer comprises N,N,N′,N′-tetrakis(3-aminopropyl)-1,12-diaminododecane and the crosslinking monomer comprises 1,3-dichloropropanol.
82 . The amine polymer of any one of claims 1 to 81 having a swelling ratio of from about 1 to about 10.
83 . The amine polymer of claim 82 wherein the swelling ratio of from about 2 to about 6.
84 . The amine polymer of claim 83 wherein the swelling ratio of from about 2 to about 4.
85 . The amine polymer of any one of claims 1 to 84 wherein the polymer is a particle having a mean diameter from about 50 microns to about 100 microns.
86 . The amine polymer of claim 85 wherein the particle is a bead.
87 . The amine polymer of claim 86 wherein the bead is a substantially spherical bead.
88 . A pharmaceutical composition comprising the amine polymer of any one of claims 1 to 87 and a pharmaceutically acceptable excipient.
89 . A method of reducing serum LDL-cholesterol in an animal subject comprising administering an effective amount of an amine polymer of any one of claims 1 to 87 or a pharmaceutical composition of claim 88 to an animal subject in need thereof.
90 . A method of treating diabetes in an animal subject comprising administering an effective amount of an amine polymer of any one of claims 1 to 87 or a pharmaceutical composition of claim 88 to an animal subject in need thereof.
91 . A method of treating Alzheimer's disease, non-alcoholic steatohepatitis, pruritus, IBS-D, or idiopathic bile acid malabsorption in an animal subject comprising administering an effective amount of an amine polymer of any one of claims 1 to 87 or a pharmaceutical composition of claim 88 to an animal subject in need thereof.
92 . A method of removing bile salts from an animal subject comprising administering an effective amount of an amine polymer of any one of claims 1 to 87 or a pharmaceutical composition of claim 88 to an animal subject in need thereof.
93 . The method of any one of claims 89 to 92 further comprising administering an agent that treats dyslipidemia to an animal subject.
94 . The method of claim 93 wherein the agent that treats dyslipidemia is a hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, a fibrate, a cholesterol absorption inhibitor, niacin (i.e. nicotinic acid or derivatives thereof), a phytosterol, an intestinal lipase inhibitor, an intestinal or secreted phospholipase A2 inhibitor, inhibitors of the synthesis or normal activity of Apo-B100, agonists of the synthesis or normal activity of ApoA, or any agent that modulates cholesterol absorption or metabolism, or a combination thereof to the animal subject.
95 . The method of claim 93 or 94 wherein the amine polymer and the agent that treats dyslipidemia, or the combination thereof are administered to the animal subject at the same time.
96 . The method of claim 93 or 94 wherein the amine polymer and the agent that treats dyslipidemia, or the combination thereof are sequentially administered to the animal subject.
97 . The method of any one of claims 94 to 96 wherein the agent that treats dyslipidemia is a HMG CoA reductase inhibitor, the HMG CoA reductase inhibitor comprising a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and a combination thereof.
98 . The method of any one of claims 94 to 96 wherein the agent that treats dyslipidemia is a fibrate, the fibrate comprising benzafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, or a combination thereof.
99 . The method of any one of claims 94 to 96 wherein agent that treats dyslipidemia is a cholesterol absorption inhibitor, the cholesterol absorption inhibitor comprising ezetimibe.
100 . The method of any one of claims 89 to 99 wherein mean serum LDL is decreased by at least 15% after 2, 4, 12, 26, 52 or more weeks of treatment with the amine polymer at a daily dose at which the subject experiences no severe gastrointestinal adverse events.
101 . The method of claim 100 wherein mean serum LDL is decreased by at least 20% after 2, 4, 12, 26, 52 or more weeks of treatment with the amine polymer at a daily dose at which the subject experiences no severe gastrointestinal adverse events.
102 . The method of claim 100 wherein mean serum LDL is decreased by at least 25% after 2, 4, 12, 26, 52 or more weeks of treatment with the amine polymer at a daily dose at which the subject experiences no severe gastrointestinal adverse events.
103 . The method of claim 100 wherein mean serum LDL is decreased by at least 30% after 2, 4, 12, 26, 52 or more weeks of treatment with the amine polymer at a daily dose at which the subject experiences no severe gastrointestinal adverse events.
104 . The method of any one of claims 89 to 99 wherein mean serum LDL is decreased by at least 15% after 2, 4, 12, 26, 52 or more weeks of treatment with the amine polymer at a daily dose of 6.0 g/day.
105 . The method of claim 104 wherein mean serum LDL is decreased by at least 20% after 2, 4, 12, 26, 52 or more weeks of treatment with the amine polymer at a dose of 6.0 g/day or less.
106 . The method of claim 104 wherein mean serum LDL is decreased by at least 25% after 2, 4, 12, 26, 52 or more weeks of treatment with the amine polymer at a dose of 6.0 g/day or less.
107 . The method of claim 104 wherein mean serum LDL is decreased by at least 30% after 2, 4, 12, 26, 52 or more weeks of treatment with the amine polymer at a dose of 6.0 g/day or less.
108 . The method of any one of claims 89 to 107 wherein the animal subject has primary hyperlipidemia or coronary heart disease.
109 . A method of improving glycemic control in an animal subject with Type II diabetes mellitus comprising administering an effective amount of an amine polymer of any one of claims 1 to 87 or a pharmaceutical composition of claim 88 to the animal subject.
110 . The method of any one of claims 89 to 109 further comprising administration of an agent that treats diabetes to the animal subject.
111 . The method of claim 110 wherein the amine polymer, the agent that treats diabetes, or the combination thereof are administered to the animal subject at the same time.
112 . The method of claim 107 wherein the amine polymer, the agent that treats diabetes, or the combination thereof are sequentially administered to the animal subject.
113 . The method of any one of claims 110 to 112 wherein the agent that treats diabetes is a sulfonylurea, a biguanide, a glitazone, a thiazolidinedione, an activator of peroxisome proliferator-activated receptors (PPARs), an alpha-glucosidase inhibitor, a potassium channel antagonist, an aldose reductase inhibitor, a glucagon antagonist, a retinoid X receptor (RXR) antagonist, a farnesoid X receptor (FXR) agonist, a FXR antagonist, glucagon-like peptide-1 (GLP-1), a GLP-1 analog, a dipeptidyl peptidase IV (DPP-IV) inhibitor, amylin, an amylin analog, an SGLT2 inhibitor, insulin, an insulin secretagogue, a thyroid hormone, a thyroid hormone analog or a combination thereof.
114 . The method of claim 113 wherein the agent that treats diabetes is a biguanide, wherein the biguanidine is metformin, buformin, phenformin, or a combination thereof.
115 . The method of claim 113 wherein the agent that treats diabetes is a thiazolidinedione, wherein the thiazolidinedione is pioglitazone, rivoglitazone, rosiglitazone, troglitazone, or a combination thereof.
116 . The method of claim 114 wherein the agent that treats diabetes is a sulfonylurea, wherein the sulfonylurea is acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glibenclamide, gliquidone, glyclopyramide, glimepiride, or a combination thereof.
117 . The method of claim 113 wherein the agent that treats diabetes is a DPP-IV inhibitor, wherein the DPP-IV inhibitor is alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin, or a combination thereof.
118 . The method of claim 113 wherein the agent that treats diabetes is a GLP-1 analog, wherein the GLP-1 analog is exenatide, liraglutide, albiglutide, or a combination thereof.
119 . The method of any one of claims 109 to 118 wherein glycated hemoglobin (Hb A1c ) is decreased by at least 0.5% after 18 weeks of treatment with the amine polymer at a daily dose at which the subject experiences no severe gastrointestinal adverse events.
120 . The method of any one of claims 109 to 118 wherein fasting plasma glucose is decreased by at least 14 mg/dL (0.8 mmol/L) after 18 weeks of treatment with the amine polymer at a daily dose at which the subject experiences no severe gastrointestinal adverse events.
121 . The method of any one of claims 109 to 118 wherein glycated hemoglobin (Hb A1c ) is decreased by at least 0.5% after 18 weeks of treatment with the amine polymer at a dose of 6.0 g/day or less.
122 . The method of any one of claims 109 to 118 wherein fasting plasma glucose is decreased by at least 14 mg/dL (0.8 mmol/L) after 18 weeks of treatment with the amine polymer at a dose of 6.0 g/day or less.
123 . The method of any one of claims 89 to 122 wherein the animal subject is a human.
124 . The method of any one of claims 89 to 123 wherein less than four unit doses of the amine polymer are administered per day.
125 . The method of any one of claims 89 to 123 wherein less than three unit doses of the amine polymer are administered per day.
126 . The method of any one of claims 89 to 123 wherein the amine polymer is administered once per day.
127 . The method of any one of claims 89 to 126 wherein the amine polymer is administered in the form of a chewable or mouth-disintegrating tablet, a liquid, a powder, a powder contained within a sachet, a soft gelatin capsule, or a hard gelatin capsule.
128 . The method of any one of claims 89 to 127 wherein a daily amount of the polymer administered once per day or twice per day has a bile acid binding capacity of at least 75% of the same daily amount of the same polymer administered three times per day.
129 . The method of claim 128 wherein a daily amount of the polymer administered once per day or twice per day has a bile acid binding capacity of at least 85% of the same daily amount of the same polymer or the same composition administered three times per day.
130 . The method of claim 128 wherein a daily amount of the polymer administered once per day or twice per day has a bile acid binding capacity of at least 95% of the same daily amount of the same polymer or the same composition administered three times per day.
131 . The method of any one of claims 89 to 130 wherein less than 25% of subjects taking the polymer once per day or twice per day experience mild or moderate gastrointestinal adverse events.
132 . The method of any one of claims 89 to 131 wherein the polymer or composition administered once a day or twice a day have about substantially the same tolerability as the same polymer or the same composition of the same daily amount administered three times a day.
133 . The method of any one of claims 128 to 132 wherein the daily amount is at least 2 grams of polymer.
134 . The method of claim 133 wherein the daily amount is at least 4 grams of polymer.
135 . The method of claim 133 wherein the daily amount is at least 6 grams of polymer.
136 . The method of any one of claims 128 to 135 wherein the sediment yield stress of the polymer is less than 4000 Pa.
137 . The method of claim 136 wherein the sediment yield stress of the polymer is less than 3000 Pa.
138 . The method of claim 136 wherein the sediment yield stress of the polymer is less than 2500 Pa.
139 . The method of any one of claims 128 to 138 wherein a mass of the polymer particles formed by hydration and sedimentation of the polymer has a viscosity of less than about 2,500,000 Pa·s, the viscosity being measured at a shear rate of 0.01 sec −1 .
140 . The method of claim 139 wherein the sedimented mass of particles has a viscosity of less than 2,000,000 Pa·s.
141 . The method of claim 139 wherein the sedimented mass of particles has a viscosity of less than 1,500,000 Pa·s.
142 . The method of claim 139 wherein the sedimented mass of particles has a viscosity of less than 1,000,000 Pa·s.
143 . The method of claim 139 wherein the sedimented mass of particles has a viscosity of less than 500,000 Pa·s.
144 . The method of any one of claims 136 to 143 wherein the polymer particles in dry form have a compressibility index of less than about 30, wherein the compressibility index is defined as 100*(TD−BD)/TD, and BD and TD are the bulk density and tap density, respectively.
145 . The method of claim 144 wherein the compressibility index is less than about 25.
146 . The method of claim 144 wherein the compressibility index is less than about 20.
147 . The method of claim 144 wherein the compressibility index is less than about 15.
148 . The method of claim 144 wherein the compressibility index is less than about 10.
149 . A process for preparing the amine polymers of any one of claims 1 to 87 comprising contacting the amine monomer with the crosslinking monomer.
150 . An amine of formula 6 having the structure:
wherein each R 25 is independently C 2 to C 8 alkylene or C 2 to C 8 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with at least one amide functional group, and R 35 is C 8 to C 16 alkylene, or C 8 to C 16 alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group.
151 . The amine of claim 150 wherein each R 25 is independently C 3 to C 6 alkylene.
152 . The amine of claim 150 wherein each R 25 is propylene.
153 . The amine of any one of claims 150 to 152 wherein R 35 is C 10 to C 14 alkylene.
154 . The amine of claim 153 wherein R 35 is decylene.
155 . The amine of claim 153 wherein R 35 is dodecylene.Join the waitlist — get patent alerts
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