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Conjugate of polyethylene glycol-polypeptide and protein drugs

A polyethylene glycol and conjugate technology, applied in the field of medicine, can solve the problems of difficult handling, gastric acid damage, poor targeting, etc., and achieve the effects of improving bioavailability, reducing the frequency of administration, and simple modification reactions

Pending Publication Date: 2022-06-28
JENKEM TECH CO LTD TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] At present, clinically, when peptide and protein drugs are administered orally, they are easily damaged by various proteases, peptidases and other hydrolysis environments after entering the digestive tract, and the drug effect is reduced or even lost. For example, some drugs are irritating to the stomach. Or acid-resistant, easy to be destroyed by gastric acid, so it is not suitable for oral administration. Its main route of administration is injection, which is directly injected into human tissues or blood vessels, without passing through the digestive system and liver, and will not be damaged by digestive juice and affected by food. The drug is absorbed quickly, the blood drug concentration rises rapidly, and the dosage is accurate. However, in clinical applications, since the drug is often distributed throughout the body after injection, the targeting of the lesion site such as tumor tissue is poor, and the bioavailability is low. Not high, the drug effect is relatively low, and adverse reactions occur quickly, and it is relatively difficult to deal with. In addition, multiple administrations are often required, and the principle of aseptic operation must be strictly followed during administration, and professionals such as doctors and nurses are required to operate , is not conducive to patient compliance, so the clinical application of drugs often encounters bottlenecks
[0003] In the prior art, researchers often use water-soluble polymers such as polyethylene glycol to modify and link drugs to prolong the physiological half-life of drugs and reduce the immunogenicity and toxicity of drugs, but the release and efficacy of drugs in the body are sometimes not ideal

Method used

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  • Conjugate of polyethylene glycol-polypeptide and protein drugs
  • Conjugate of polyethylene glycol-polypeptide and protein drugs
  • Conjugate of polyethylene glycol-polypeptide and protein drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0255] Example 1: Synthesis of Linker (L)

[0256]

[0257] BOC-amino acid (92.2 mmol) and N,N-dicyclohexylcarbodiimide (DCC, 23.8 g, 115.3 mmol) were added to dichloromethane (500 mL), cooled in an ice-water bath, and p-hydroxybenzyl alcohol ( 11.4 g, 92.2 mmol), remove the ice bath after the addition, and react at room temperature overnight. Filtration, the filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness to obtain the crude product, which was purified by column chromatography to obtain product 1.

[0258] 1a: 19.7 g, yield 76.0%. 1 H NMR: (CDCl 3 ): 8.75(s, 1H), 7.22(d, 2H), 7.05(d, 2H), 4.87(s, 2H), 3.74(s, 2H), 1.52(s, 9H).

[0259] 1b: 20.3 g, yield 74.8%. 1 H NMR: (CDCl 3 ): 8.74(s, 1H), 7.21(d, 2H), 7.05(d, 2H), 4.88(s, 2H), 3.77(m, 1H), 1.51(s, 9H), 1.27(d, 3H) .

[0260] 1c: 21.6 g, yield 72.5%. 1 H NMR: (CDCl 3 ): 8.75(s, 1H), 7.22(d, 2H), 7.05(d, 2H), 4.87(s, 2H), 3.61(d, 1H), 2,82(m, 1H), 1.52(s, 9H), 1.06(d, 6H). ...

Embodiment 2

[0265] Example 2: Synthesis of the conjugate of monomethoxy polyethylene glycol acetic acid and linking chain (mPEG-L-40K)

[0266]

[0267] Monomethoxy polyethylene glycol-acetic acid (mPEG-CM, 40K, 5 g, 0.125 mmol), compound L (0.25 mmol, prepared in Example 1) and 1-hydroxybenzotriazole (HOBt, 16.9 mg, 0.125 mmol) was added to the reaction flask, dissolved in dichloromethane, then diisopropylethylamine (45.2 mg, 0.35 mmol) was added, stirred well, and after cooling in an ice bath, (EDCI, 47.9 mg, 0.25 mmol) was added in batches ), after the addition, the system naturally rose to room temperature and reacted overnight. The next day after concentration, the residue was crystallized with isopropanol, filtered with suction, and dried to obtain the product mPEG-L.

[0268] mPEG-L1 (40K): 4.6 g, yield 92.4%.

[0269] mPEG-L2 (40K): 4.5 g, yield 90.8%.

[0270] mPEG-L3 (40K): 4.7 g, yield 93.7%.

Embodiment 3

[0271] Example 3: Preparation of Linker Chain L5

[0272] The synthetic route of linking chain L5 is shown below:

[0273]

[0274] Synthesis of compound (2):

[0275] 3,4-Dihydroxybenzaldehyde (10g, 72.5mmol) was dissolved in acetonitrile (150mL), sodium bicarbonate (8g, 94.3mmol) was added, the temperature was raised to 60°C, benzyl bromide (12.4g, 72.5mmol) was added, then The temperature was raised to 80°C and stirred overnight. Concentrate to remove acetonitrile, add 10% aqueous hydrochloric acid (200 mL) to the residue, extract with ethyl acetate (150 mL*3), combine, dry, filter, concentrate, and the residue is purified by column chromatography to obtain 10 g of off-white solid (yield: 60 g) %). 1 H NMR: (CDCl 3 ): δ9.82(s, 1H), 7.48-7.40(m, 7H), 7.05(m, 1H), 6.02(s, 1H), 5.21(s, 2H).

[0276] Synthesis of compound (3):

[0277] Compound (2) (5 g, 21.9 mmol) was dissolved in DMF (80 mL), potassium carbonate (7.6 g, 54.75 mmol), potassium iodide (0.73 g, 4.38 mmo...

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Abstract

The invention discloses a conjugate of polyethylene glycol-polypeptide and a protein drug, and particularly relates to a conjugate of polyethylene glycol-interleukin (such as interleukin 2), in the conjugate, the drug such as interleukin 2 can be degraded and separated from the conjugate structure, slow release and controlled release can be realized, the drug administration frequency is reduced, and the drug delivery efficiency is improved. The bioavailability of the medicine and the compliance of a patient are greatly improved. Particularly, the inventor of the invention carries out deeper research on the coupling degree of the conjugate to obtain the conjugate or a mixture thereof with clear coupling degree, which is beneficial to the optimization of subsequent drug effect and the research of pharmacology.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular to a combination of polyethylene glycol-polypeptide and protein drugs, in particular to a combination of polyethylene glycol and interleukin (eg, interleukin-2). Background technique [0002] At present, in clinical practice, when polypeptide and protein drugs are administered orally, they are easily damaged by various proteases, peptidases and other hydrolysis environments after entering the digestive tract, and the efficacy of the drugs is reduced or even lost. For example, some drugs are irritating to the stomach. Or not acid-resistant, easily destroyed by gastric acid, so it is not suitable for oral administration. The main route of administration is injection, which is directly injected into human tissues or blood vessels, without going through the digestive system and liver, and will not be damaged by digestive juices and food. The drug is absorbed quickly, the blood ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K47/54A61K45/00A61K38/20A61P35/00A61P37/02A61P31/12A61P31/04
CPCA61K47/60A61K47/543A61K47/545A61K45/00A61K38/2013A61P35/00A61P37/02A61P31/12A61P31/04A61K31/704A61K47/54C07C215/08C07C229/08C07D249/04C08G65/333C08G65/48
Inventor 王庆彬宋艳萍冯泽旺汪进良熊艳丽赵宣
Owner JENKEM TECH CO LTD TIANJIN
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