Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Linker compound, polyethylene glycol-linker compound and derivatives thereof and polyethylene glycol-linker-drug conjugate

A polyethylene glycol and compound technology, applied in the field of medicine, can solve the problems of low bioavailability, unfavorable patient compliance, reducing drug immunogenicity and toxicity, etc.

Active Publication Date: 2018-11-02
JENKEM TECH CO LTD (LIAONING)
View PDF7 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] At present, clinically, many drugs are not suitable for oral administration (for example, when polypeptide and protein drugs are administered orally, they will be damaged by various proteases, peptidases and other hydrolytic environments after they enter the digestive tract, and the drug efficacy will be reduced or even lost. For example, some drugs are irritating to the stomach or are not resistant to acid and are easily destroyed by gastric acid), the 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 affected by digestive juice. Influenced by destruction and 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 rapidly after injection, the targeting of the lesion site such as tumor tissue Poor, low bioavailability, relatively low drug efficacy, and rapid adverse reactions, relatively difficult to deal with, in addition, often require multiple doses, and the principles of aseptic operation must be strictly followed when administering, requiring professionals If doctors and nurses operate, it 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Linker compound, polyethylene glycol-linker compound and derivatives thereof and polyethylene glycol-linker-drug conjugate
  • Linker compound, polyethylene glycol-linker compound and derivatives thereof and polyethylene glycol-linker-drug conjugate
  • Linker compound, polyethylene glycol-linker compound and derivatives thereof and polyethylene glycol-linker-drug conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0181] Example 1 Synthesis of Linking Chain (L)

[0182]

[0183] 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.

[0184] 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).

[0185] 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) .

[0186] 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,...

Embodiment 2

[0191] Example 2 Synthesis of the combination of monomethoxy polyethylene glycol acetic acid and linking chain (mPEG-L(40K))

[0192]

[0193] Monomethoxy polyethylene glycol-acetic acid (mPEG-CM, 40K, 5 g, 0.125 mmol), compound L (0.25 mmol, prepared in Example 1)

[0194] and 1-hydroxybenzotriazole (HOBt, 16.9 mg, 0.125 mmol) were added to the reaction flask, dissolved in dichloromethane, and then diisopropylethylamine (45.2 mg, 0.35 mmol) was added, stirring uniformly, 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 the reaction was carried out overnight. The next day after concentration, the residue was crystallized with isopropanol, filtered with suction, and dried to obtain the product mPEG-L.

[0195] mPEG-L1 (40K): 4.6 g, yield 92.4%.

[0196] mPEG-L2 (40K): 4.5 g, yield 90.8%.

[0197] mPEG-L3 (40K): 4.7 g, yield 93.7%.

Embodiment 3

[0198] Example 3 Preparation of monomethoxy polyethylene glycol-doxorubicin conjugate (mPEG-L-Dox(40K))

[0199]

[0200] Compound mPEG-L (0.075 mmol, prepared in Example 2) was added to the reaction flask, dissolved in dichloromethane (30 mL), N 2 Cool under protection, add succinimidyl carbonate (23.0 mg, 0.09 mmol), stir to dissolve, then add triethylamine (10.1 mg, 0.1 mmol), remove the cooling bath after the addition, and react at room temperature overnight. The reaction solution was concentrated, and the residue was crystallized with isopropanol to obtain the product mPEG-L-NHS.

[0201] mPEG-L1-NHS (40K): 2.6 g, yield 88.5%.

[0202] mPEG-L2-NHS (40K): 2.7 g, yield 89.2%.

[0203] mPEG-L3-NHS (40K): 2.6 g, yield 87.9%.

[0204] Compound mPEG-L-NHS (0.06 mmol, prepared above) was dissolved in dichloromethane (25 mL), N 2 Cool under protection, add diisopropylethylamine (12.9 mg, 0.1 mmol), stir evenly, then add doxorubicin hydrochloride (52.2 mg, 0.09 mmol), and s...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a linker compound, a polyethylene glycol-linker compound and derivatives thereof and a polyethylene glycol-linker-drug conjugate. The linker compound and a conjugate with polyethylene glycol and derivatives thereof can be used for drug modification. Moreover, the modification reaction is simple and is easily carried out, the reaction yield is high, and the application rangeof the modified drug is wide. The modified drug is gradually degraded from a conjugate chain in vivo and can achieve longer retention time at lesions (such as cancer suffering parts), the slow release and controlled release aims are achieved, the administration frequency can be reduced, and the bioavailability of the drug and patient compliance are greatly improved.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular to a linker compound, a polyethylene glycol-linker combination and derivatives thereof, a polyethylene glycol-linker-drug combination and a pharmaceutical composition and application thereof. Background technique [0002] At present, in clinical practice, many drugs are not suitable for oral administration due to reasons such as oral administration of polypeptide and protein drugs, after entering the digestive tract, they will be damaged by various proteases, peptidases and other hydrolysis environments, and their efficacy will be reduced or even lost. For example, some drugs are irritating or acid-intolerant to the stomach and are easily destroyed by gastric acid), and their 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 affected by digestive j...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07C229/08C07C215/08C07D249/04C08G65/333A61K47/54A61K47/60A61K31/704A61P35/00
CPCA61K31/704A61K47/542A61K47/543A61K47/545A61K47/60A61P35/00C07C215/08C07C229/08C07D249/04C08G65/33306C08G65/33317Y02P20/55
Inventor 冯泽旺汪进良宋艳萍熊艳丽赵宣
Owner JENKEM TECH CO LTD (LIAONING)
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com