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

PEG-leuprolide conjugate and preparation method thereof

A technology for leuprolide and conjugates, applied in the field of PEG-leuprolide conjugates and their synthesis, can solve the problems of large losses, many synthesis steps, etc., and achieves small losses, easy commercialization, and synthetic routes short effect

Inactive Publication Date: 2020-01-03
NANKAI UNIV
View PDF3 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to many synthesis steps, the loss is large

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
  • PEG-leuprolide conjugate and preparation method thereof
  • PEG-leuprolide conjugate and preparation method thereof
  • PEG-leuprolide conjugate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0028] The present invention provides a new PEG-leuprolide conjugate and its synthesis method, through the direct reaction of monomethoxypolyethylene glycol succinimide active ester with unprotected leuprolide to obtain leuprolide PEG-leuprolide conjugate (I or II) modified by the imidazole group on the 2-position histidine of propylidene, the reaction formula is shown in the figure below:

[0029]

[0030] In the present invention, the leuprolide includes leuprolide and leuprolide acetate. The structure of the active ester of monomethoxy polyethylene glycol succinimide is CH 3 O-(CH 2 CH 2 O)x-(CH 2 CH 2 )y-NHS; x is an integer value of 10 to 1300, the structure of polyethylene glycol includes linear structure and branched structure, and the molecular weight is 400-60KDa; y is an integer value of 0, 0.5, 1 to 5, including monomethyl Carbonate, acetate, propionate, succinate, valerate, etc. of oxypolyethylene glycol succinimide. In the reaction, the molar ratio of leu...

Embodiment 1

[0035] Preparation of PEG-leuprolide conjugate (PEG2K-LEU):

[0036] 12.6 mg (0.01 mmol) of leuprolide acetate was dissolved in 5 mL of distilled water, and an equimolar amount of CH was added 3 O-(CH 2 CH 2 O) 45 -CH 2 CH 2 -NHS, reacted at 37°C for 4 hours, purified by cation exchange chromatography, purification conditions: 20mM pH 6.5PBS, sodium chloride gradient: 0-0.5M, collected target peaks for dialysis, and freeze-dried to obtain PEG2K-LEU. MALDI-TOF mass spectrometry detection shows that the molecular weight is 3235.6, which is exactly equal to the sum of the molecular weights of leuprolide and PEG, indicating that only one PEG chain is attached to each leuprolide molecule ( figure 1) . Dissolve PEG2K-LEU in deuterated water, do 1 H NMR spectrum ( figure 2); Compared with leuprolide, the chemical shift of the hydrogen on the imidazole group moves to the high field, indicating that the PEG segment is connected to the imidazole group of the 2-position histidi...

Embodiment 2

[0038] Preparation of PEG-leuprolide conjugate (PEG5K-LEU):

[0039] 12.6 mg (0.01 mmol) of leuprolide acetate was dissolved in 5 mL of distilled water, and an equimolar amount of CH was added 3 O-(CH 2 CH 2 O) 110 -CH 2 CH 2 -NHS, reacted at 37°C for 6 hours, purified by cation exchange chromatography, purification conditions: 20mM pH6.5PBS, sodium chloride gradient: 0-0.5M, collected target peaks for dialysis, and freeze-dried to obtain PEG5K-LEU. MALDI-TOF mass spectrometry detection shows that the molecular weight is 6144.2, which is exactly equal to the sum of the molecular weights of leuprolide and PEG, indicating that only one PEG chain is attached to each leuprolide molecule ( figure 1) . Dissolve PEG5K-LEU in deuterated water, do 1 H NMR spectrum ( figure 2) ; Compared with leuprolide, the chemical shift of the hydrogen on the imidazole group moves to the high field, indicating that the PEG segment is connected to the imidazole group of the 2-position histid...

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

PropertyMeasurementUnit
molecular weightaaaaaaaaaa
Login to View More

Abstract

The invention provides a novel PEG-leuprolide conjugate and a preparation method thereof. The preparation method comprises the steps that a methoxy-polyethylene glycol succinimide active ester directly reacts with unprotected leuprolide to obtain imidazolyl-modified PEG-leuprolide conjugate on the histidine 2-D-histidine. The conjugate retains leuprolide activity, a half-life period is extended, plasma clearance is reduced, and pharmacokinetic properties are improved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a PEG-leuprolide conjugate and a synthesis method thereof. Background technique [0002] Leuprolide is a polypeptide composed of nine amino acids, and its amino acid sequence is: GLP-HIS-TRP-SER-TYR-DLEU-LEU-ARG-PRO-NHET, which is a synthetic gonadotropin-releasing hormone ( GnRH, also known as luteinizing hormone releasing hormone, LHRH) analogs, its activity is much higher than natural GnRH. In short-term use, due to its agonistic effect on gonadotropin-releasing hormone receptors, it can promote the secretion of gonadotropins from the pituitary gland, and the secretion of steroid hormones from the testes or ovaries. When used for a long time, due to the influence of receptor down-regulation, the secretion of gonadotropins is inhibited, thereby inhibiting the secretion of steroid hormones by reproductive organs. Therefore, leuprolide is clinically used to treat or alleviate...

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
Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K38/09A61P35/00A61P15/00
CPCA61K47/60A61K38/09A61P35/00A61P15/00
Inventor 张拥军付免关英
Owner NANKAI UNIV
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