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A combination of polyethylene glycol-polypeptide and protein drugs

A technology of polyethylene glycol and conjugates, applied in the field of medicine, can solve problems such as difficult handling, gastric acid damage, and poor targeting, and achieve the effects of improving bioavailability, reducing dosing frequency, and simple modification reactions

Active Publication Date: 2022-02-18
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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  • A combination of polyethylene glycol-polypeptide and protein drugs
  • A combination of polyethylene glycol-polypeptide and protein drugs
  • A combination of polyethylene glycol-polypeptide and protein drugs

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 polyethylene glycol-polypeptide and protein drugs, in particular a conjugate of polyethylene glycol-interleukin (such as interleukin 2), in which the drug such as interleukin 2 It can be degraded and separated from the structure of the conjugate, which can realize sustained release and controlled release, reduce the frequency of administration, and greatly improve the bioavailability of the drug and the patient's compliance. In particular, the inventors of the present invention conducted a more in-depth study on the coupling degree of the conjugate, and obtained a conjugate or a mixture thereof with a definite degree of coupling, which is beneficial to the optimization of subsequent drug efficacy and pharmacological research.

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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Patent Type & Authority Patents(China)
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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