Crosslinked polydiallymine copolymers for the treatment of type 2 diabetes

Patent metadata

Field	Value
Publication number	US-11267924-B2
Application number	US-201514971424-A
Country	US
Kind code	B2
Filing date	Dec 16, 2015
Priority date	Dec 18, 2014
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

Polydiallylamine copolymers are copolymers comprising monomers of polydiallylamine and either polyvinlyamine or polyallylamine. Polydiallylamine copolymers are often crosslinked. The polydiallyamine copolymers are useful as pharmaceutical compositions and may be used in the treatment of type 2 diabetes and for mitigating the complications of type 2 diabetes.

First claim

The invention claimed is:

1. A polydiallylamine block copolymer comprising a plurality of polymer chains, wherein each polymer chain is according to Formula (I):

wherein:
u, and v are each independently an integer from 0 to 200,000; and
w is an integer from 1 to 200,000;
A, B, C and D are each independently repeat units selected from Formula (II) or Formula (III);
wherein Formula (II) is according to the structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
m is 0 or 1;
n is an integer from 1 to 200,000;

and Formula (III) is according to the structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
o is 0 or 1;
p is an integer from 1 to 200,000;

R 1 and R 2 and R 3 and R 4 are each independently selected from a group consisting of
H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl,
(C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl,
(C 1 -C 10 )alkylamine, —O(O)C—(C 1 -C 10 )alkyl, (C 1 -C 10 )alkyl-COOH,
(C 3 -C 10 )cycloalkyl-COOH, —(O)CH 3 , —OH, amide,
a guanidino group represented by Formula (A)

wherein a is an integer from 0 to 25,

a guanidinium chloride group represented by Formula (B),

wherein b is an integer from 0 to 25,

a guanidinobenzene group represented by Formula (C),

wherein c is an integer from 0 to 25,

a dihydroxy group, represented by Formula (D),

wherein d is an integer from 0 to 25,

a polyethylene glycol group, represented by Formula (E)

wherein e is an integer from 1 to 400,

a group represented by Formula (F)

wherein R z and R y are each independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl,
(C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl,
(C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, —O(O)C-(C 1 -C 10 )alkyl,
(C 1 -C 10 )alkyl-COOH, (C 3 -C 10 )cycloalkyl-COOH, —(O)CH 3 , —OH and
amide,

a group represented by Formula (G)

wherein R x and R w are each independently selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl,
(C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl,
(C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylannine, —O(O)C—(C 1 -C 10 )alkyl,
(C 1 -C 10 )alkyl-COOH, (C 3 -C 10 )cycloalkyl-COOH, —(O)CH 3 , cyano, cyano(C 1 -C 10 )alkyl, —OH and
amide,

and a point of attachment to another repeat unit of the copolymer;

and wherein:
(a) each polymer chain must be cross-linked with at least one other polymer chain, and
(b) each polymer chain may be internally cross-linked; and

wherein the molar ratio of Formula (II) monomer:Formula (III) monomer in the polydiallylamine copolymer is from 99:1 to 1:99, and the ratio of cross-linked repeat units:un-cross-linked repeat units is from 1:99 to 50:50.

2. The copolymer according to claim 1 , wherein each m is 0.

3. The copolymer according to claim 1 , wherein each m is 0 and each o is 1.

4. The copolymer according to claim 1 , wherein the ratio of Formula (II) monomer:Formula (III) monomer is from 90:10 to 5:95.

5. The copolymer according to claim 1 , wherein the copolymers has been cross-linked with a cross-linking agent.

6. The copolymer according to claim 5 , wherein the cross-linking agent is selected from epichlorohydrin, epibromohydrin, (iodomethyl)oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1,2-epoxybutane, bromo-1,2-epoxybutane, 1,2-dibromoethane, 1-bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, tris(2-chloroethyl)amine, and bis(2-chloroethyl)methylamine, 1,3-butadiene diepoxide, 1,5-hexadiene diepoxide, diglycidyl ether, 1,2,7,8-diepoxyoctane, 1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N,N-diglycidylaniline, neopentyl glycol diglycidyl ether, diethylene glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene, resorcinol digylcidyl ether, 1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1,4-cyclohexanedimethanol diglycidyl ether, 1,3-bis-(2,3-epoxypropyloxy)-2-(2,3-dihydroxypropyloxy)propane, 1,2-cyclohexanedicarboxylic acid diglycidyl ester, 2,2′-bis(glycidyloxy)diphenylmethane, bisphenol F diglycidyl ether, 1,4-bis(2′,3′-epoxypropyl)perfluoro-n-butane, 2,6-di(oxiran-2-ylmethyl)-1, 2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindol-1,3,5,7-tetraone, bisphenol A diglycidyl ether, ethyl 5-hydroxy-6,8-di(oxiran-2-ylmethyl)-4-oxo-4h-chromene-2-carbo xylate, bis[4-(2,3-epoxy-propylthio) phenyl]-sulfide, 1,3-bis(3-glycidoxypropyl)tetramethyldisiloxane, 9,9-bis[4-(glycidyloxy) phenyl]fluorene, triepoxyisocyanurate, glycerol triglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniline, isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R)-triglycidyl ester, triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycerol propoxylate triglycidyl ether, triphenylolmethane triglycidyl ether, 3,7,14-tris[[3-(epoxypropoxy)propyl]dimethylsilyloxy]-1, 3,5,7,9,11,14-heptacyclopentyltricyclo[7.3.3.15,11]heptasiloxane, 4,4′-methylenebis(N, N-diglycidylaniline), bis(halomethyl)benzene, bis(halomethyl)biphenyl and bis(halomethyl)naphthalene.

7. The copolymer according to claim 6 , wherein the cross-linking agent is epichlorohydrin.

Assignees

• Genzyme Corp

Inventors

• Dhal Pradeep K
• Miller Robert J
• Polomoscanik Steven C
• Larsen Philip Just
• Huebschle Thomas
• Schmidt Thorsten
• Davison Ian
• Mcdonnell Peter D
• Agbugba Chinyere

Classifications

• A61K31/785 Primary

  Polymers containing nitrogen · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C08F226/02

  by a single or double bond to nitrogen · CPC title

• C08K5/1515

  Three-membered rings · CPC title

• C08F226/04

  Diallylamine · CPC title