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Polyethylene glycol-cactus oligopeptide bonded rapamycin derivative

一种化合物、多羧基的技术，应用在雷帕霉素衍生物领域，能够解决易反应不完全、反应产物复杂化、负载率降低等问题

Active Publication Date: 2015-03-25
JENKEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the large molecular structure of rapamycin and two active hydroxyl groups in the molecular structure, it is easy to react incompletely when it is esterified with polyethylene glycol pawpaw oligopeptide, and a rapamycin may also appear. The phenomenon of mymycin linking multiple polyethylene glycol molecules, resulting in a decrease in the loading rate and complexity of the reaction product, and at the same time, the linking group between the PEG molecule and the oligopeptide in the above literature is not disclosed -CO-CH 2 - the linking group

Method used

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  • Polyethylene glycol-cactus oligopeptide bonded rapamycin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Example 1 Preparation of glycine rapamycin ester

[0108]

[0109] Add tert-butyl bromoacetate (5.82g, 30mmoL) to the reaction flask, dissolve it with acetone (80mL), then add a solution of sodium azide (4.55g, 70mmoL) dissolved in water (40mL), and heat to reflux overnight. The reaction solution was evaporated to remove acetone, and the residue was extracted with ether. The extract was washed with saturated brine, dried, and concentrated under reduced pressure to obtain an oily liquid. This liquid was dissolved in methanol (90 mL), and 1N sodium hydroxide solution (90 mL) was added, stirred, and heated to reflux for 3 h. After cooling, the methanol was evaporated under reduced pressure, the remaining night was cooled in an ice bath, and 6N hydrochloric acid was added to adjust the pH to 2, and then extracted with ether. The extract was washed with water, dried, and concentrated to obtain azidoacetic acid, MS m / z: 124[ M+Na] + .

[0110] Add azidoacetic acid (253mg, 2.5mmo...

Embodiment 2

[0112] Example 2 Preparation of monomethoxy polyethylene glycol (number average molecular weight 20000)-rapamycin conjugate (LPR-1)

[0113]

[0114] Mix monooxypolyethylene glycol acetic acid (20K, 1g, 0.05mmoL), glycine rapamycin ester (97mg, 0.1mmoL) prepared in Example 1, and 1-hydroxybenzotriazole (HOBt, 6.8mg, Add 0.05mmoL) and DMAP (12.2mg, 0.1mmoL) to the reaction flask, dissolve with dichloromethane, cool in an ice bath, and then drop in a solution of DCC (15.5mg, 0.075mmoL) dissolved in dichloromethane. It was naturally raised to room temperature and reacted overnight. The next day, the reaction solution was concentrated, and the residue was crystallized with isopropanol to obtain monomethoxy polyethylene glycol (20K)-rapamycin conjugate (LPR-1) 0.82g (n Approximately 450).

[0115] 1 H-NMR(300MHz, CDCl 3 ): 0.90 (Me, 3H, 43), 0.92 (Me, 3H, 49), 0.94 (Me, 3H, 46), 0.96 (Me, 3H, 48), 0.97 (Me, 3H, 45), 1.10 (CH 2 , 2H, 24), 1.11(CH 2 , 2H, 36), 1.20(CH 2 , 2H, 42), 1.33(C...

Embodiment 3

[0116] Example 3 Preparation of monomethoxy polyethylene glycol (number average molecular weight 20000)-glutamic acid dipeptide-rapamycin conjugate (LPR-2)

[0117]

[0118] The monomethoxypolyethylene glycol-glutamic acid dipeptide (20K, 0.5g, 0.025mmol), 48.6mg (0.05mmol) of glycine rapamycin ester prepared in Example 1, HOBt (3.4mg, 0.025mmoL) ) And DMAP 6.1mg (0.05mmoL) were added to the reaction flask, dissolved in dichloromethane, cooled in an ice bath, and then dripped with a solution of 15.5mg (0.075mmol) of DCC dissolved in dichloromethane, and naturally warmed to room temperature after dripping , React overnight. The next day, the reaction solution was concentrated, and the residue was crystallized with isopropanol to obtain monomethoxy polyethylene glycol (20K)-glutamic acid dipeptide-rapamycin conjugate (LPR-2) 0.41g (n about For 450).

[0119] 1 H-NMR(300MHz, CDCl 3 ): 0.90 (Me, 9H, 43), 0.92 (Me, 9H, 49), 0.94 (Me, 9H, 46), 0.96 (Me, 9H, 48), 0.97 (Me, 9H, 45), 1.10...

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Abstract

The invention provides a compound shown in the formula I in the specification and pharmaceutically acceptable salts of the compound, the preparation method of the compound and pharmaceutically acceptable salts of the compound and a medicine composition containing the compound shown in the formula I or the pharmaceutically acceptable salts of the compound. In the compound provided by the invention, each end group of the polyethylene glycol molecule is capable of bonding with a plurality of rapamycin molecules through cactus oligopeptide, and the medicine loading rate is improved. The compound can be used for inducing immunosuppression and treating transplant rejection, self-immune diseases, solid tumors, fungal infection and cardiovascular and cerebrovascular diseases.

Description

Technical field [0001] The invention relates to a polyethylene glycol-polyclaw oligopeptide bonded rapamycin derivative, a preparation method thereof and a pharmaceutical composition containing them. The present invention also relates to the application of such compounds to induce immunosuppression and treatment of transplant rejection, graft-to-host diseases, autoimmune diseases, inflammation, adult T-cell leukemia / lymphoma, solid tumors, fungal infections, cardiovascular diseases, Cerebrovascular disease, peripheral vascular disease or vascular hyperproliferation disease. Background technique [0002] Rapamycin (also known as "sirolimus") is a triene macrolide antibiotic produced by Streptomyces hygroscopicus found in the soil of Easter Island in Chile in 1975. Rapamycin has antifungal activity, especially against Candida albicans, both in vivo and in vitro. Rapamycin has significant immunosuppressive activity and can prevent allergic encephalomyelitis, multiple sclerosis and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48A61K47/48A61K31/436A61P35/00A61P35/02A61P9/14A61P9/00A61P37/06A61P19/02A61P29/00A61P31/10A61P25/00A61P11/00
CPCC07D498/18C08G65/331C08G2650/30C08G65/3311C08G65/33303C08G65/33396C08L2203/02A61K47/65A61K47/60A61P11/00A61P19/02A61P25/00A61P29/00A61P31/10A61P35/00A61P35/02A61P37/00A61P37/06A61P9/00A61P9/14A61K31/436
Inventor 贾健欢冯泽旺汪进良刘岩王振国赵宣
Owner JENKEM TECH
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