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Conjugate of polyethylene glycol-polypeptide and protein drug

A polyethylene glycol and conjugate technology, applied in the field of medicine, can solve the problems of reducing drug immunogenicity and toxicity, adverse patient compliance, poor targeting, etc.

Active Publication Date: 2019-04-09
JENKEM TECH CO LTD (LIAONING)
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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 drug
  • Conjugate of polyethylene glycol-polypeptide and protein drug
  • Conjugate of polyethylene glycol-polypeptide and protein drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0259] Example 1: Synthesis of Linker Chain (L)

[0260]

[0261] Add BOC-amino acid (92.2mmol) and N,N-dicyclohexylcarbodiimide (DCC, 23.8g, 115.3mmol) into dichloromethane (500mL), cool in an ice-water bath, then add p-hydroxybenzyl alcohol ( 11.4 g, 92.2 mmol), the ice bath was removed after the addition, and the reaction was carried out overnight at room temperature. After filtration, the filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness to obtain a crude product, which was purified by column chromatography to obtain product 1.

[0262] 1a: 19.7g, 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).

[0263] 1b: 20.3g, 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) .

[0264] 1c: 21.6g, 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

[0269] Embodiment 2: the synthesis of the conjugate (mPEG-L-40K) of monomethoxypolyethylene glycol acetic acid and connecting chain

[0270]

[0271] Monomethoxypolyethylene glycol-acetic acid (mPEG-CM, 40K, 5g, 0.125mmol), compound L (0.25mmol, prepared in Example 1) and 1-hydroxybenzotriazole (HOBt, 16.9mg, 0.125mmol) into the reaction flask, dissolved in dichloromethane, then added diisopropylethylamine (45.2mg, 0.35mmol), stirred evenly, and added in batches after cooling in an ice bath (EDCI, 47.9mg, 0.25mmol ), after the addition, the system naturally rose to room temperature and reacted overnight. After concentrating the next day, the residue was crystallized with isopropanol, filtered with suction, and dried to obtain the product mPEG-L.

[0272] mPEG-L1 (40K): 4.6 g, yield 92.4%.

[0273] mPEG-L2 (40K): 4.5g, yield 90.8%.

[0274] mPEG-L3 (40K): 4.7g, yield 93.7%.

Embodiment 3

[0275] Example 3: Preparation of linking chain L5

[0276] The synthetic route of linker chain L5 is as follows:

[0277]

[0278] Synthesis of compound (2):

[0279] 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, and Raise the temperature to 80°C and stir overnight. Concentrate to remove acetonitrile, add 10% hydrochloric acid aqueous solution (200mL) to the residue, extract with ethyl acetate (150mL*3), combine and dry, filter, concentrate, and the residue is purified by column chromatography to obtain off-white solid 10g (yield 60 %). 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).

[0280] Synthesis of compound (3):

[0281] Compound (2) (5g, 21.9mmol) was dissolved in DMF (80mL), potassium carbonate (7.6g, 54.75mmol), potassium iodide (0.73g, 4.38mmol) were ad...

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Abstract

The invention discloses a conjugate of a polyethylene glycol-polypeptide and protein drug, and particularly relates to a conjugate of a polyethylene glycol-interleukin (such as interleukin 2). In theconjugate, the drug such as interleukin2 can be separated from the structure of the conjugate to achieve sustained release and controlled release, thereby reducing the frequency of drug administration, and greatly improving the bioavailability of the drug and patient compliance. Particularly, the inventors conduct a more in-depth study on the degree of coupling of the conjugate to obtain conjugates having definite degrees of coupling or a mixture thereof, which is advantageous for optimization of subsequent effects and pharmacological studies.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a polyethylene glycol-polypeptide and protein drug conjugate, in particular to a polyethylene glycol-interleukin (such as interleukin 2) conjugate. Background technique [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 rapid...

Claims

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Application Information

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IPC IPC(8): A61K47/60A61K38/20A61P35/00A61P37/02A61P31/12A61P31/04
CPCA61K38/2013A61K47/60A61P31/04A61P31/12A61P35/00A61P37/02A61K31/704
Inventor 王庆彬宋艳萍冯泽旺汪进良熊艳丽赵宣
Owner JENKEM TECH CO LTD (LIAONING)
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