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Nucleophilic catalysts for oxime linkage

A nucleophilic, catalyst technology, applied in sexual diseases, digestive system, allergic diseases, etc., can solve problems such as accelerated oxime linkage, aniline toxicity, short reaction time, etc.

Inactive Publication Date: 2013-10-23
BAXALTA GMBH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although aniline catalysis can accelerate oxime attachment, allowing short reaction times and the use of low concentrations of aminoxy reagents, aniline is toxic, which must be considered when e.g. conjugated therapeutic proteins form drug bases

Method used

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  • Nucleophilic catalysts for oxime linkage
  • Nucleophilic catalysts for oxime linkage
  • Nucleophilic catalysts for oxime linkage

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0262] Preparation of homobifunctional linker NH 2 [OCH 2 CH 2 ] 2 ONH 2

[0263] Homobifunctional linker NH 2 [OCH 2 CH 2 ] 2 ONH 2

[0264]

[0265] According to Boturyn et al. (Tetrahedron 1997; 53:5485-92), in the two-step organic reaction of Gabriel-Synthesis using modified primary amines ( image 3 ) to synthesize (3-oxa-pentane-1,5-dioxyamine) containing two active aminooxy groups. In the first step, one molecule of 2,2-chloroether is reacted with two molecules of endo-N-hydroxy-5-norbornene-2,3-dicarboximide in dimethylformamide (DMF) . The desired homobifunctional product was prepared from the resulting intermediate by hydrazinolysis in ethanol.

Embodiment 2

[0267] Preparation of homobifunctional linker NH 2 [OCH 2 CH 2 ] 4 ONH 2

[0268] Homobifunctional linker NH 2 [OCH 2 CH 2 ] 4 ONH 2

[0269]

[0270] According to Boturyn et al. (Tetrahedron 1997; 53:5485-92), in the two-step organic reaction of the Gabriel synthesis using modified primary amines ( image 3 ) to synthesize (3,6,9-trioxa-undecane-1,11-dioxylamine) containing two active aminooxy groups. In the first step, one bis-(2-(2-chloroethoxy)-ethyl)-ether molecule is combined with two endo-N-hydroxy-5-norbornene-2,3-diformyl Amine molecules react in DMF. The desired homobifunctional product was prepared from the resulting intermediate by hydrazinolysis in ethanol.

Embodiment 3

[0272] Preparation of homobifunctional linker NH 2 [OCH 2 CH 2 ] 6 ONH 2

[0273] Homobifunctional linker NH 2 [OCH 2 CH2] 6 ONH 2

[0274]

[0275] (3,6,9,12, 15-pentaoxa-heptadecane-1,17-dioxylamine). In the first step, one molecule of hexaethylene glycol dichloride reacts with two molecules of endo-N-hydroxy-5-norbornene-2,3-dicarboximide in DMF. The desired homobifunctional product was prepared from the resulting intermediate by hydrazinolysis in ethanol.

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Abstract

The invention relates to materials and methods of conjugating a water soluble polymer to an oxidized carbohydrate moiety of a therapeutic protein comprising contacting the oxidized carbohydrate moiety with an activated water soluble polymer under conditions that allow conjugation. More specifically, the present invention relates to the aforementioned materials and methods wherein the water soluble polymer contains an active aminooxy group and wherein an oxime or hydrazone linkage is formed between the oxidized carbohydrate moiety and the active aminooxy group on the water soluble polymer, and wherein the conjugation is carried out in the presence of a nucleophilic catalyst.

Description

field of invention [0001] The present invention relates to materials and methods for conjugating water-soluble polymers to proteins. Background of the invention [0002] Preparation of conjugates by forming a covalent linkage between a water-soluble polymer and a therapeutic protein can be performed by a variety of chemistries. Pegylation of polypeptide drugs protects the drug during circulation and improves its pharmacodynamic and pharmacokinetic profile (Harris and Chess, Nat Rev Drug Discov. 2003; 2:214-21). The pegylation process attaches repeating units of ethylene glycol (polyethylene glycol (PEG)) to polypeptide drugs. PEG molecules have a large hydrodynamic volume (5-10 times the size of globular proteins), are highly water soluble and can be hydrated, are nontoxic, nonimmunogenic and are rapidly cleared by the body. Pegylation of molecules can lead to increased drug resistance to enzymatic degradation, increased half-life in vivo, less frequent dosing, reduced imm...

Claims

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Application Information

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IPC IPC(8): A61K47/48
CPCA61K47/48215A61K47/4823A61K47/61A61K47/60A61P1/16A61P15/08A61P17/00A61P19/08A61P19/10A61P25/00A61P35/00A61P35/02A61P37/02A61P37/04A61P43/00A61P5/00A61P5/06A61P5/24A61P7/00A61P7/02A61P7/04A61P7/06A61P9/00A61P9/02A61P3/10A61K38/00A61K47/18
Inventor J·西克曼S·海德尔H·罗滕施泰纳A·伊文思P·图雷切克O·卓耶奇林
Owner BAXALTA GMBH