Multi-armed forms of activated polyoxazoline and methods of synthesis thereof

• US 8,088,884 B2
• Filed: 09/29/2008
• Issued: 01/03/2012
• Est. Priority Date: 09/27/2007
• Status: Active Grant

• Current Assignee: Serina Therapeutics, Inc.
• Original Assignee: Serina Therapeutics, Inc.
• Inventors: Harris, J. Milton, Bentley, Michael David, Yoon, Kunsang, Fang, Zhihao
• Primary Examiner(s): Wu, David W
• Assistant Examiner(s): JONES JR., ROBERT STOCKTON
• Application Number:
  US12/680,448
• Publication Number:
  US 20100249368A1
• Time in Patent Office: 1,191 Days
• Field of Search: 424/78.08, 424/78.36, 424/78.38, 424/178.1, 424/179.1, 424/193.1, 424/194.1, 424/280.1, 525/410, 525/411, 525/417, 525/540, 528/403, 528/417, 528/422, 528/423
• US Class Current: 528/423
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: C07D 263/12 with radicals containing only hydrogen and carbon atoms
• CPC Class Codes: C08G 73/0233 Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups
• CPC Class Codes: C08L 79/02 Polyamines

Abstract

The present disclosure provides novel POZ-2 derivatives, methods for synthesizing POZ-2 derivatives and intermediates useful in such methods. In one embodiment, the POZ-2 derivative comprises two linear POZ chains of the present disclosure linked directly or indirectly to a branching moiety that contains a functional group for linking the POZ-2 derivative to the target molecule. Target molecule-POZ-2 conjugates are also described. In certain embodiment, the POZ-2 derivatives have low polydispersity values and a decreased amount of impurities produced by unwanted side reactions, such as, but not limited to, chain transfer.

Claims

1. An activated polyoxazoline-2 (POZ-2) derivative of the general structure

2. The POZ-2 derivative of claim 1 wherein R₂ has from 1 to 12 carbon atoms.

3. The POZ-2 derivative of claim 1 wherein R₂ is methyl, ethyl or n-propyl.

4. The POZ-2 derivative of claim 1 wherein at least one of POZ_a and POZ_b of the POZ-2 derivative has a polydispersity value of less than or equal to 1.2, less than or equal to 1.1 or less than or equal to 1.05.

5. The POZ-2 derivative of claim 1 wherein the POZ-2 derivative is a monofunctional POZ-2 derivative.

6. The POZ-2 derivative of claim 1 wherein X is selected from the groups consisting of carboxylic acid, active esters, carbonates, aldehyde, oxyamine, acetylene, isocyanates, isothiocyanate, amines, alcohol, tresylate (2,2,2-trifluorethylsulfonate), vinylsulfone, iodoacetamide, pyridyldisulfide, ketones, azide, hydrazide and maleimide.

7. The POZ-2 derivative of claim 1 wherein the linkage with the target molecule is a hydrolytically stable linkage.

8. The POZ-2 derivative of claim 1 wherein the functional group is protected.

9. The POZ-2 derivative of claim 1 wherein L(I), L(II) and L(III) are each independently selected from —

NH—

, substituted or unsubstituted alkyl groups or substituted or unsubstituted alkenyl groups.

10. The POZ-2 derivative of claim 1 wherein A is H or a substituted or unsubstituted alkyl group.

11. The POZ derivative of claim 1 wherein Br is a C atom and c is 1 and L(I) contains a substituted or unsubstituted aryl group.

12. The POZ derivative of claim 1 wherein Br is a C atom and c is 1, d is 1 and at least one of L(I) and L(II) contains a substituted or unsubstituted aryl group.

13. A target molecule-POZ-2 conjugate of the general formula A-B-TM, wherein

A is a POZ-2 derivative of claim 1 minus any leaving groups eliminated during the reaction of the active functional group on the POZ-2 derivative with a binding partner on a target molecule;

TM is a target molecule, the target molecule containing the binding partner; and

B is a hydrolytically stable linkage formed between the active functional group and the binding partner.

14. The target molecule-POZ-2 conjugate of claim 13 wherein the active functional group is an Iodoacetamide, the binding partner is SH and B is a thioether linkage, the active functional group is a maleimide, the binding partner is SH and B is a thioether linkage, the active functional group is an active carbonate, the binding partner is NH₂ and B is a urethane linkage, the active functional group is an active ester, the binding partner is NH₂ and B is an amide linkage or the active functional group is an aldehyde, the binding partner is NH₂ and B is an amine linkage.

15. The target molecule POZ-2 conjugate of claim 13 wherein the in vivo half-life of the target molecule-POZ-2 conjugate is increased under physiological conditions.

16. The target molecule POZ-2 conjugate of claim 13 wherein at least one POZ chain of the POZ-2 derivative has a polydispersity value of less than or equal to 1.2, less than or equal to 1.1 or less than or equal to 1.05.