Crosslinked polydiallymine copolymers for the treatment of type 2 diabetes

Patent metadata

Field	Value
Publication number	US-2016177019-A1
Application number	US-201514971424-A
Country	US
Kind code	A1
Filing date	Dec 16, 2015
Priority date	Dec 18, 2014
Publication date	Jun 23, 2016
Grant date	—

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

1 . A copolymer comprising a polymer chain 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;
R 1 and R 2 are each independently a pharmaceutically acceptable end group or a point of attachment to another repeat unit of the copolymer;

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 3 and R 4 are each independently a pharmaceutically acceptable end group or a point of attachment to another repeat unit of the copolymer;

with the provisio that the copolymer of Formula (I) is not exclusively a polymer of Formula (II) or exclusively a polymer of Formula (III).

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

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

4 . The copolymer according to any one of claims 1 to 3 , wherein each o is 0.

5 . The copolymer according to any one of claims 1 to 3 , wherein each o is 1.

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

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

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

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

10 . The copolymer according to any one of claims 1 to 9 , wherein 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 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, or
a group represented by Formula (G)

wherein R x and R w 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 , cyano, cyano(C 1 -C 10 )alkyl, —OH, amide, or
or a point of attachment to another repeat unit on the copolymer.

11 . The copolymer according to any one of claims 1 to 10 , wherein the ratio of Formula (I):Formula (II) is from 99:1 to 1:99.

12 . The copolymer according to any one of claims 1 to 11 , wherein the ratio of Formula (I):Formula (II) is from 90:10 to 5:95.

13 . The copolymer according to any one of claims 1 to 12 , wherein the ratio of Formula (I):Formula (II) is from 12.5:87.5 to 87.5:12.5.

14 . The copolymer according to any one of claims 1 to 13 , wherein the ratio of Formula (I):Formula (II) is from 25:75 to 75:25.

15 . The copolymer according to any one of claims 1 to 14 , wherein the copolymer is cross-linked with a cross-linking agent.

16 . The copolymer according to claim 15 , wherein the cross-linking agent is a multifunctional multivalent amine specific reagent.

17 . The copolymer according to claim 16 , wherein the multifunctional multivalent amine specific reagent comprises two or more electrophilic groups.

18 . The copolymer according to claim 17 , wherein the multifunctional multivalent amine specific reagent is selected from the group consisting of halide, aldehyde, ketone, acid halide, acid active ester, epoxide, acrylate, methacrylate, arylsulfonate, alkylsulfonate, and vinyl sulfone

19 . The copolymer according to claim 15 , 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-carboxylate, 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 i

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P39/04

  Chelating agents · CPC title