Branched polyethylene glycol iso-bifunctional derivative, as well as preparation method and two-component biological related substance conjugate thereof

A bifunctional, polyethylene glycol technology, applied in the field of two-component bio-related substance conjugates and branched polyethylene glycol heterobifunctional derivatives, can solve the problem of prolonging the action time of drugs and unable to target positioning. function, increase steric hindrance, etc., to reduce the degree of inactivation or hydrolysis by enzymes, prolong the action time, and increase the effect of steric hindrance

Active Publication Date: 2018-09-14
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention aims at the disadvantages in the prior art that the two different functional groups of heterofunctionalized polyethylene glycol are distributed at both ends of the polyethylene glycol component, which causes the targeted drug to be far away from the therapeutic drug and cannot effectively exert the targeting and positioning function. The invention provides a branched polyethylene glycol heterobifunctional derivative. Two different functional groups are placed on the same side of the branched polyethylene glycol component, so that the modified two different biologically related substances can be The adjusted and close spatial distribution can make the pharmacological molecules contact the lesion site at the same time of targeting, and exert the drug effect faster and more effectively; and the branched polyethylene glycol is more effective than the linear polyethylene glycol. The structure provides more effective protection. Compared with linear polyethylene glycol with the same molecular weight, due to its special molecular shape, polyethylene glycol with branched chains can form an umbrella-shaped protective layer on the surface of the drug, increasing the The steric hindrance around the drug molecule can prevent other macromolecular substances from attacking the drug more effectively than linear polyethylene glycol, reduce the degree of inactivation or hydrolysis of the drug in the body, and prolong the action time of the drug in the body

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  • Branched polyethylene glycol iso-bifunctional derivative, as well as preparation method and two-component biological related substance conjugate thereof
  • Branched polyethylene glycol iso-bifunctional derivative, as well as preparation method and two-component biological related substance conjugate thereof
  • Branched polyethylene glycol iso-bifunctional derivative, as well as preparation method and two-component biological related substance conjugate thereof

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preparation example Construction

[0271] For related preparation methods, reference may be made to the preparation methods and reaction conditions in the prior art. Including but not limited to the types of chemical reactions involved in documents CN104530417A, CN104877127A, WO / 2016 / 206540A, CN201610252378X and the cited documents.

[0272] For those who do not have a suitable pre-modification form for the target functional group when coupling the nitrogen branching center and the polyethylene glycol chain, it is also possible to conduct a pair of terminal heterofunctional groups based on the prepared branched polyethylene glycol heterobifunctional derivatives. Chemical modification is achieved. The suitable pre-modified form refers to the one that can be converted into the target functional group through micro-modification, and can keep the structure unchanged during the preparation process, especially when the azo branching center and the polyethylene glycol chain are coupled, without causing side reactions ...

Embodiment 1

[1062] Embodiment 1 Lysine branched polyethylene glycol derivative (α-N)

[1063]

[1064] Among them, the corresponding general formula (2) PEG a 、PEG b Both are mPEG structure, L A , L B Both are ethylene groups, U is a nitrogen atom, L d Does not exist, G is a tertiary carbon, F 1 , F 2 One of them is COOH, the other is (CH 2 ) 4 NH 2 , with F 1 for COOH, F 2 for (CH 2 ) 4 NH 2 For example, R 01 for COOH, Z 1 does not exist, R 02 for NH 2 ,Z 2 For 1,4-butylene. Both PEGs have a molecular weight of 20 kDa, for a total molecular weight of approximately 40 kDa.

[1065] Step a: Lys(Cbz)-OH hydrochloride was washed with a small amount of water, and dried to obtain mono-protected lysine S1-1 (Lys(Cbz)-OH) from which the hydrochloride was removed. 1 H NMR (CDCl 3 ): 1.24-1.60 (-CH 2 CH 2 CH 2 CH2 NH-Cbz,2H),5.10(Cbz,-CH 2 -, 2H), 7.2 to 7.4 (Cbz, Ph-, 5H).

[1066] Step b: Alkylation reaction of 30 mmol monoprotected lysine small molecule S1-1 with me...

Embodiment 2

[1070] Embodiment 2 glycine branched polyethylene glycol derivatives

[1071]

[1072] Among them, the corresponding general formula (2) PEG a 、PEG b Both are mPEG structure, L A , L B Both are ethylene groups, U is a nitrogen atom, L d for CH 2 CONH, G is tertiary carbon, F 1 , F 2 One of them is COOH, the other is (CH 2 ) 4 NH 2 , with F 1 for COOH, F 2 for (CH 2 ) 4 NH 2 For example, R 01 for COOH, Z 1 does not exist, R 02 for NH 2 ,Z 2 For 1,4-butylene. Both PEGs have a molecular weight of 10 kDa, for a total molecular weight of about 20 kDa.

[1073] Step a: Lys(Cbz)-OMe hydrochloride was washed with a small amount of water, and dried to obtain mono-protected lysine S2-1 (Lys(Cbz)-OMe) from which the hydrochloride was removed. 1 H NMR (CDCl 3 ): 1.24-1.60 (-CH 2 CH 2 CH 2 CH2 NH-Cbz,2H),3.72(-COOCH 3 ,3H),5.10(Cbz,-CH 2 -, 2H), 7.2 to 7.4 (Cbz, Ph-, 5H).

[1074] Step b: Alkylation reaction of 30mmol glycine and methoxypolyethylene glycol me...

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Abstract

The invention discloses a branched polyethylene glycol iso-bifunctional derivative, as well as a preparation method and a two-component biological related substance conjugate thereof. The structure ofthe branched polyethylene glycol iso-bifunctional derivative is shown as a general formula (1) and contains i (more than or equal to 2) alkoxy-terminated PEG chains, U is a branched center of a valence state i+1, Ld does not exist or becomes a bivalent linking group, and the iso-bifunctional end is composed of a trivalent branched center G and two different functional ends F1 and F2 and respectively independently contains a plurality of functional end groups R01 and R02 of the same type. Two functional groups of the branched polyethylene glycol iso-bifunctional derivative are positioned on the same side of the branched polyethylene glycol component, a product of the conjugated biological related substance is a branched polyethylene glycol two-component biological related substance, the functional groups are conjugated with two different biological related substances and are uniformly distributed on the same side of the polyethylene glycol component, and the derivative is capable of improving properties of targeted drugs, optically marked drugs and the like and is expected to be applied to the field of drug combination. The structural formula is as shown in the description.

Description

technical field [0001] The invention relates to the field of polymer synthesis, in particular to a branched polyethylene glycol heterobifunctional derivative, a preparation method thereof and a two-component bio-related substance conjugate. Background technique [0002] PEGylation is one of the important means of drug modification. Among them, functionalized polyethylene glycol (PEG) can use its active groups to interact with drug molecules (including protein drugs and organic small molecule drugs), peptides, sugars, lipids, oligonucleotides, affinity ligands, etc. Coupling of body, cofactor, liposome and biomaterials through covalent bonds to achieve PEGylation of drugs and other biologically related substances. The modified drug molecules will have many excellent properties of polyethylene glycol, such as hydrophilicity, flexibility, anticoagulation and so on. In addition, due to the steric repulsion effect, PEG-modified drugs can avoid glomerular filtration and biologic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/333C08G65/334
CPCC08G65/33396C08G65/3348
Inventor 闫策翁文桂刘超姜琰琰周纯
Owner XIAMEN SINOPEG BIOTECH
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