Alkylated amine polymers

• US 5,693,675 A
• Filed: 06/05/1995
• Issued: 12/02/1997
• Est. Priority Date: 06/10/1994
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: GelTex Pharmaceuticals, Inc. (Sanofi )
• Inventors: Holmes-Farley, Stephen Randall, Mandeville, W. Harry III
• Primary Examiner(s): Mosley, Terressa
• Application Number:
  US08/461,298
• Time in Patent Office: 911 Days
• Field of Search: 514/742, 525/328.2, 525/523, 525/359.5, 525/359.3, 525/359.1, 528/421, 528/422
• US Class Current: 514/742
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61K 31/787 containing heterocyclic rings having nitrogen as a ring hetero atom
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: C08F 220/00 Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
• CPC Class Codes: C08F 220/60 containing nitrogen in addition to the carbonamido nitrogen
• CPC Class Codes: C08F 226/02 by a single or double bond to nitrogen
• CPC Class Codes: C08F 26/00 Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
• CPC Class Codes: C08F 26/02 by a single or double bond to nitrogen
• CPC Class Codes: C08F 8/00 Chemical modification by after-treatment graft polymers, block polymers, crosslinking with unsaturated monomers or with polymers C08F251/00 - C08F299/00; of conjugated diene rubbers C08C
• CPC Class Codes: C08F 8/02 Alkylation
• CPC Class Codes: C08F 8/44 Preparation of metal salts or ammonium salts
• CPC Class Codes: C08L 39/02 Homopolymers or copolymers of vinylamine

Abstract

The invention relates to alkylated amine polymers and a method for removing bile salts from a patient that includes administering to the patient a therapeutically effective amount of product produced by a process comprising alkylating one or more crosslinked amine polymers, salts or copolymers thereof with at least one alkylating agent. The reaction product is characterized in that: (i) at least some of the nitrogen atoms are unreacted with alkylating agent; and (ii) less than 10 mol % of the nitrogen atoms in the polymer react with the alkylating agent to form quaternary ammonium units.

Claims

1. An alkylated crosslinked polymer comprising the reaction product of:

a) one or more crosslinked polymers, salts or copolymers thereof characterized by a repeat unit selected from the group consisting of;

##STR3## where n is a positive integer and each R, independently, is H or a C₁ -C₈ alkyl group; and

b) at least one aliphatic alkylating agent, said reaction product characterized in that;

(i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; and

(ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units.

16. The polymer of claim 1 wherein said alkylating agent comprises a C₁ -C₂₀ alkyl halide.

17. The polymer of claim 16 wherein said alkyl halide is a C₄ -C₁₈ alkyl halide.

18. The polymer of claim 1 wherein said alkylating agent comprises a C₁ -C₂₀ dihaloalkane.

19. The polymer of claim 18 wherein said dihaloalkane is a 1,10-dihalodecane.

20. The polymer of claim 1 wherein said alkylating agent comprises a C₁ -C₂₀ hydroxyalkyl halide.

21. The polymer of claim 20 wherein said hydroxyalkyl halide is an 11-halo-1-undecanol.

22. The polymer of claim 1 wherein said alkylating agent comprises a C₁ -C₂₀ alkyl halide ammonium salt.

23. The polymer of claim 22 wherein said alkyl halide ammonium salt is a C₄ -C₁₂ haloalkyl trimethylammonium salt.

24. The method of claim 1 wherein said alkylating agent comprises a C₁ -C₂₀ alkyl epoxy ammonium salt.

25. The polymer of claim 24 wherein said alkyl epoxy ammonium salt is a (glycidylpropyl)trimethylammonium salt.

26. The polymer of claim 1 wherein said alkylating agent comprises a C₁ -C₂₀ epoxy alkylamide.

27. The polymer of claim 26 wherein said epoxy alkylamide is selected from the group consisting of N-(2,3-epoxypropane)butyramide, N-(2,3-epoxypropane)hexanamide, and combinations thereof.

28. The polymer of claim 1 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents has the formula RX where R is a C₁ -C₂₀ alkyl group and X is one or more electrophilic leaving groups, and the other of said alkylating agents has the formula R'"'"'X where R'"'"' is a C₁ -C₂₀ alkyl ammonium group and X is one or more electrophilic leaving groups.

29. The polymer of claim 28 wherein one of said alkylating agents is an alkyl halide and the other of said alkylating agents is an alkyl halide ammonium salt.

30. The polymer of claim 29 wherein said alkyl halide is a C₄ -C₂₀ alkyl halide and said alkyl halide ammonium salt is a C₄ -C₁₈ alkyl halide ammonium salt.

31. The polymer of claim 29 wherein said alkyl halide is a C₁₀ alkyl halide and said alkyl halide ammonium salt is a C₆ alkyl halide ammonium salt.

32. The polymer of claim 1 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents has the formula RX where R is a C₁ -C₂₀ alkyl group and X is one or more electrophilic leaving groups, and the other of said alkylating agents has the formula R'"'"'X where R'"'"' is a C₁ -C₂₀ hydroxyalkyl group and X is one or more electrophilic leaving groups.

33. The polymer of claim 32 wherein one of said alkylating agents is an alkyl halide and the other of said alkylating agents is a hydroxyalkyl halide.

34. The polymer of claim 1 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents is a C₁ -C₂₀ dihaloalkane and the other of said alkylating agents is a C₁ -C₂₀ alkylammonium salt.

2. An alkylated crosslinked polymer comprising the reaction product of:

a) one or more crosslinked polymers, salts or copolymers thereof characterized by a repeat unit having the formula ##STR4## where n is a positive integer and each R, independently, is H or a C₁ -C₈ alkyl group; and

b) at least one aliphatic alkylating agent, said reaction product characterized in that;

(i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; and

(ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units.

3. The polymer of claim 2 wherein said polymer is crosslinked by means of a multifunctional crosslinking agent, said agent being present in an amount from about 0.5-25% by weight, based upon the combined weight of monomer and crosslinking agent.

4. The polymer of claim 2 wherein said crosslinking agent is present in an amount from about 2.5-20% by weight, based upon the combined weight of monomer and crosslinking agent.

5. The polymer of claim 2 wherein said crosslinking agent comprises epichlorohydrin.

6. The polymer of claim 2 wherein said polymer, salt or copolymer thereof is characterized by a repeat unit having the formula ##STR5##

7. The polymer of claim 2 wherein said alkylating agent has the formula RX where R is a C₁ -C₂₀ alkyl, C₁ -C₂₀ hydroxyalkyl, C₁ -C₂₀ alkylammonium, or C₁ -C₂₀ alkylamido group and X is one or more electrophilic leaving groups.

8. The polymer of claim 7 wherein X is a halide, epoxy, tosylate, or mesylate.

9. The polymer of claim 2 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents has the formula RX where R is a C₁ -C₂₀ alkyl group and X is one or more electrophilic leaving groups, and the other of said alkylating agents has the formula R'"'"'X where R'"'"' is a C₁ -C₂₀ alkyl ammonium group and X is one or more electrophilic leaving groups.

10. The polymer of claim 9 wherein one of said alkylating agents having the formula RX is an alkyl halide and the other of said alkylating agents having the formula R'"'"'X is an alkyl halide ammonium salt.

11. The polymer of claim 10 wherein said alkyl halide is a C₄ -C₂₀ alkyl halide and said alkyl halide ammonium salt is a C₄ -C₁₈ alkyl halide ammonium salt.

12. The polymer of claim 10 wherein said alkyl halide is a C₁₀ alkyl halide and said alkyl halide ammonium salt is a C₆ alkyl halide ammonium salt.

13. The polymer of claim 2 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents has the formula RX where R is a C₁ -C₂₀ alkyl group and X is one or more electrophilic leaving groups, and the other of said alkylating agents has the formula R'"'"'X where R'"'"' is a C₁ -C₂₀ hydroxyalkyl group and X is one or more electrophilic leaving groups.

14. The polymer of claim 13 wherein one of said alkylating agents is an alkyl halide and the other of said alkylating agents is a hydroxy alkyl halide.

15. The polymer of claim 2 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents is a C₁ -C₂₀ dihaloalkane and the other of said alkylating agents is a C₁ -C₂₀ alkylammonium salt.

35. The polymer of claim 6 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents is a C₁₀ alkyl halide and the other of said alkylating agents is a C₆ alkyl halide ammonium salt.

36. An alkylated crosslinked polymer comprising the reaction product of:

a) one or more crosslinked polymers, salts or copolymers thereof characterized by a repeat unit selected from the group consisting of;

##STR6## where n is a positive integer and each R, independently, is H or a C₁ -C₈ alkyl group; and

b) at least one aliphatic alkylating agent, said reaction product characterized in that;

(i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent;

(ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units; and

(iii) said polymer is crosslinked by means of a multifunctional crosslinking agent, said agent being present in an amount from 1-10% by weight based upon the combined weight of monomer and crosslinking agent.

37. An alkylated crosslinked polymer comprising the reaction product of:

a) one or more crosslinked polymers, salts or copolymers thereof characterized by a repeat unit selected from the group consisting of;

##STR7## where n is a positive integer and each R, independently, is H or a C₁ -C₈ alkyl group; and

b) at least one hydrophobic aliphatic alkylating agent, said reaction product characterized in that;

(i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; and

(ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units.

38. An alkylated crosslinked polymer comprising the reaction product of:

a) one or more crosslinked polymers, salts or copolymers thereof characterized by a repeat unit selected from the group consisting of;

##STR8## where n is a positive integer and each R, independently, is H or a C₁ -C₈ alkyl group; and

b) at least one alkylating agent, having the formula RX wherein R is a C₁ -C₂₀ alkylammonium group and X is an electrophilic leaving group, said reaction product characterized in that;

(i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; and

(ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units.