Electrophilic polyethylene oxides for the modification of polysaccharides, polypeptides (proteins) and surfaces

• US 5,650,234 A
• Filed: 09/09/1994
• Issued: 07/22/1997
• Est. Priority Date: 09/09/1994
• Status: Expired due to Term

• Current Assignee: Biosurface Engineering Technologies, Inc. (Ferring Holding SA), ISI Norgren Inc., Surface Engineering Technologies Division of Innerdyne Incorporated
• Original Assignee: Surface Engineering Technologies Division of Innerdyne Incorporated
• Inventors: Tsang, Ray, Hu, Chen-Ze, Dolence, Eric Kurt, Sanders, Clifton G., Osaki, Shigemasa
• Primary Examiner(s): KRASS, FREDERICK F
• Application Number:
  US08/304,656
• Time in Patent Office: 1,047 Days
• Field of Search: 525/408, 525/403, 525/54.1, 525/54.2, 525/54.21, 428/447, 427/452, 427/2, 527/200, 527/207, 530/350, 530/362, 530/363, 530/380, 530/381, 530/405, 530/406, 530/345, 536/21, 536/29.1, 548/520, 548/435, 548/465, 548/475, 548/542, 548/259, 548/296, 546/208, 546/243
• US Class Current: 428/447
• CPC Class Codes: C07D 207/46 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 239/34 One oxygen atom
• CPC Class Codes: C07D 239/36 as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 249/18 Benzotriazoles
• CPC Class Codes: C07K 1/1077 by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/3328 heterocyclic
• CPC Class Codes: C08G 65/33317 heterocyclic
• CPC Class Codes: Y10T 428/31663 As siloxane, silicone or silane

Abstract

Several poly(ethylene glycol) mixed carbonates and their preparation are closed. These carbonates are synthesized by conversion of polyethylene glycol first to the chloroformate then by reaction with the hydroxyl group of N-hydroxybenzotriazole or 2-hydroxypyrimidine or N-hydroxy-2-pyrrolidinone. These mixed carbonate analogs smoothly react with amino groups in aminoglycans and protein and amino containing surfaces to form stable, hydrolysis resistant carbamate linkages.

Claims

1. A compound of the formula:

##STR6## wherein R₁ is selected from an N-benzotriazole group, an N-2-pyrrolidinone group, or an 2-oxypyrimidine group;

R₂, R₃ and R₄ are independently selected alkylene groups of about 2 to about 3 carbon atoms and may be the same or different;

R₅ is selected from hydrogen, methyl, a carbonyloxy-N-benzotriazole group, a carbonyloxy-N-2-pyrrolidinone group, and a carbonyl-2-oxypyrimidine group;

a is an integer from 1 to 1000 and each of b and c is an integer from 0 to 1000, where a+b+c is an integer from 3 to 1000.

2. A compound of claim 1, where R₂, R₃ and R₄ are independently --CH₂ CH₂ -- or --CH₂ CH(CH₃)-- or a combination thereof.

3. A compound of claim 2 wherein R₂, R₃ and R₄ are --CH₂ CH₂ --.

4. A compound of claim 3 wherein R₅ is selected so as to give a homobifunctional compound.

5. A method for the covalent bonding of a bioactive compound selected from an aminoglycan polysaccharide, a peptide and a protein to a polymeric surface using a polyoxyalkylene tether which comprises contacting a substrate having an amine-grafted polymeric surface having free amino groups with a compound of claim 1 under conditions whereby said R₅ group of the compound of claim 1 reacts with a free amino group of the polymeric surface forming a covalent bond to give a modified polymeric surface having activated polyoxyalkylene groups covalently bonded thereto;

and contacting the modified polymeric surface with the bioactive compound, under conditions whereby said bioactive compound is covalently bonded to said tether and wherein said polymeric surface comprises a membrane formed from plasma polymerization of a hydrocyclosiloxane monomer of the general formula ##STR7## wherein R is an aliphatic group having 1 to about 5 carbon atoms and n is an integer from 2 to about 10.

6. A method according to claim 5 wherein said hydrocyclosiloxane monomer is selected from the group consisting of 1,3,5,7-tetramethylhydrocyclotetrasiloxane, 1,3,5,7,9-pentamethylhydrocyclopentasiloxane, 1,3,5,7,9,11-hexamethylhydrocyclohexasiloxane, and a mixture of 1,3,5,7,9-pentamethylcyclopentasiloxane and 1,3,5,6,9,11-hexamethylcyclohexasiloxane monomers.

7. A method according to claim 6 wherein said free amino groups are grafted on the polymeric surface by reaction with a gas of an N-protected unsaturated or cyclic amine within a plasma chamber under plasma grafting reaction conditions.

8. A method according to claim 7 wherein said N-protected unsaturated or cyclic amine is trimethylsilylallylamine.

9. A method of preparing a thromboresistant coating which comprises

(a) contacting an object having an amine grafted polymeric surface having primary amine groups with a compound of claim 1;

and

(b) contacting the object with a solution of heparin,

wherein said polymeric surface comprises a membrane formed from plasma polymerization of a hydrocyclosiloxane monomer of the general formula ##STR8## where R is an aliphatic group having 1 to about 5 carbon atoms and n is an integer from 2 to about 10.

10. A thromboresistant coating made by the method of claim 9.

11. A thromboresistant coating which comprises a membrane formed from the plasma polymerization of hydrocyclosiloxane monomer of the general formula:

##STR9## where R is an aliphatic group having 1 to about 5 carbon atoms and n is an integer from 2 to about 10, covalently linked by a carbamate linkage to one end of a polyoxyalkylene tether wherein the tether is covalently linked at its other end by a carbamate linkage to a heparin molecule, which is prepared by coupling a compound of claim 1 with a free amine group of the membrane, followed by coupling to heparin.

12. A thromboresistant coating according to claim 11 wherein said hydrocyclosiloxane monomer is selected from the group consisting of 1,3,5,7-tetramethylhydrocyclotetrasiloxane, 1,3,5,7,9-pentamethylhydrocyclopentasiloxane, 1,3,5,7,9,11-hexamethylhydrocyclohexasiloxane, and a mixture of 1,3,5,7,9-pentamethylcyclopentasiloxane and 1,3,5,6,9,11-hexamethylcyclohexasiloxane monomers.

13. A thromboresistant coating according to claim 12 wherein said polyoxyalkylene tether is a polyethyleneglycol.

14. A thromboresistant coating according to claim 13 wherein said polyethylene glycol has a molecular weight of about 500 to 20,000.

15. A substrate polymeric coating having a bioactive compound covalently attached by a polyoxyalkylene tether to the polymeric surface which comprises a membrane formed from the plasma polymerization of hydrocyclosiloxane monomer of the general formula:

##STR10## where R is an aliphatic group having 1 to about 5 carbon atoms and n is an integer from 2 to about 10, covalently linked by a carbamate linkage to one end of a polyoxyalkylene tether wherein the tether is covalently linked at its other end by a carbamate linkage to a bioactive molecule, which is prepared by coupling a compound of claim 1 with a free amine group of the membrane, followed by coupling to the bioactive molecule.

16. A coating according to claim 15 wherein said bioactive compound is selected from the group consisting of an aminoglycan polysaccharide, a polypeptide, a protein, a compound halving antithrombotic or thrombolytic properties and a metal chelator.

17. A coating according to claim 16 wherein said bioactive compound is selected from the group consisting of heparin, tissue plasminogen activator, streptokinase, a prostaglandin, an antiplatelet drug and deferoxamine.

18. A coating according to claim 15 wherein said hydrocyclosiloxane monomer is selected from the group consisting of 1,3,5,7-tetramethylhydrocyclotetrasiloxane, 1,3,5,7,9-pentamethylhydrocyclopentasiloxane, 1,3,5,7,9,11-hexamethylhydrocyclohexasiloxane, and a mixture of 1,3,5,7,9-pentamethylcyclopentasiloxane and 1,3,5,6,9,11-hexamethylcyclohexasiloxane monomers.

19. A coating according to claim 18 wherein said polyoxyalkylene tether is a polyethyleneglycol.

20. A coating according to claim 19 wherein said polyethylene glycol has a molecular weight of about 500 to 20,000.

21. A modified polymeric surface made according to the method of claim 5.