Conjugates of saturated aliphatic chain alcohol, dexamethasone, and Glu-Asp-Gly, preparation, nano structure, and applications thereof

A technology of -glu-asp-gly and dexamethasone, applied in the field of structure, can solve the problems of osteoporosis side effects, limited treatment objects and regimens, low bioavailability, etc., and achieves broad application prospects and excellent immunosuppressive effects. Effect

Inactive Publication Date: 2014-12-17
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the shortcomings of these drugs such as easy degradation, low bioavailability, strong side effects, and limited treatment targets and programs, research on new immunosuppressants has always been valued.
The inventors have realized that glucocorticoids have strong immunosuppressive activity on the one hand and osteoporosis side effects on the other hand

Method used

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  • Conjugates of saturated aliphatic chain alcohol, dexamethasone, and Glu-Asp-Gly, preparation, nano structure, and applications thereof
  • Conjugates of saturated aliphatic chain alcohol, dexamethasone, and Glu-Asp-Gly, preparation, nano structure, and applications thereof
  • Conjugates of saturated aliphatic chain alcohol, dexamethasone, and Glu-Asp-Gly, preparation, nano structure, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031]Embodiment 1 prepares dexamethasone 3-formyl propionate (1)

[0032] 3.93g (10mmol) dexamethasone reacted with 1.3g (13mmol) succinic anhydride in 150ml tetrahydrofuran (THF) in the presence of 1.46g (12mmol) 4-dimethylaminopyridine (DMAP) in the dark for 48 hours, TLC (CH 2 Cl 2 :CH 3 OH:HOAC, 20:1:0.15) showed complete disappearance of starting material. Add 30ml H to the reaction mixture 2 O, concentrated under reduced pressure, the residue was added KHSO 4 The pH was adjusted to 2, and the precipitated colorless powder was washed with acetone / petroleum ether to obtain 4.64 g (94%) of the title compound as a colorless powder. ES I / MS(m / z)491[M-H] - . 1 H NMR (300MHZ, DMSO-d6): δ / ppm=7.29(d, J=10.2Hz, 1H), 6.23(d, J=9.3Hz, 1H), 6.01(s, 1H), 5.42(s, 1H ), 5.17(s, 1H), 5.05(d, J=17.7Hz, 1H), 4.80(d, J=17.7Hz, 1H), 4.15(m, 1H), 2.88(m, 1H), 2.52(m , 2H), 2.61(m, 3H), 2.34(m, 2H), 2.15(m, 2H), 1.77(m, 1H), 1.61(m, 2H), 1.49(s, 3H), 1.35(m, 1H), 1.08 (m, 1H), 0.88 ...

Embodiment 2

[0033] Embodiment 2 prepares dexamethasone 3-N-formylsuccinimidyl propionate (2)

[0034] 4.92g (10mmol) dexamethasone succinate (1) was present in 2.50g (13mmol) 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (HCl·EDC) Under reaction with 1.50g (13mmol) N-hydroxysuccinimide (HOSu) in the solvent of 100ml THF and 10ml DMF dark reaction 24 hours, TLC (CH 2 Cl 2 :CH 3 OH:HOAC, 30:1:0.15) showed complete disappearance of starting material. The reaction mixture was concentrated under reduced pressure, 150ml of ethyl acetate was added to the residue, and the resulting solution was washed with 20ml of saturated NaHCO 3 Wash 3 times with aqueous solution, wash 2 times with 20ml saturated NaCl aqueous solution, wash with 20ml saturated KHSO 4 The aqueous solution was washed 3 times, then washed 2 times with 20ml saturated NaCl aqueous solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduc...

Embodiment 3

[0035] Embodiment 3 prepares Boc-Gly-O-(CH 2 ) 7 CH 3 (3a)

[0036] 0.875 g (5 mmol) of Boc-Gly was dissolved in 20 mL of anhydrous THF, and 0.675 g (5 mmol) of N-hydroxybenzotriazole (HOBt) was added to the resulting solution under ice cooling to completely dissolve it. After 10 minutes, 1.236 g (6 mmol) of dicyclohexylcarbodiimide (DCC) was added to obtain reaction solution I. Put 0.78g (6mmol) CH in ice bath 3 (CH 2 ) 7 OH was suspended in 20 mL of anhydrous dichloromethane, and then 1 mL of N-methylmorpholine (NMM) was added to adjust the pH to 9. Stir for 35 minutes to obtain reaction solution II. The reaction solution I was added to the reaction solution II under ice-cooling, first stirred under ice-cooling for 1 h, and then stirred at room temperature for 12 h, TLC (ethyl acetate:petroleum ether, 2:1) showed that Boc-Gly disappeared. Dicyclohexylurea (DCU) was filtered off, concentrated under reduced pressure, and the residue was dissolved in 50 mL of ethyl acet...

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PUM

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Abstract

The invention relates to conjugates of saturated aliphatic chain alcohol, dexamethasone, and Glu-Asp-Gly, preparation, a nano structure, and applications thereof. The invention discloses 6 saturated aliphatic chain alcohol modified dexamethasone-Glu-Asp-Gly conjugates represented by the formula 10 a-f, wherein in the formula the n represents 7, 9, 11, 13, 15, or 17. The invention also discloses a preparation method, a nano structure, immunity inhibition activity, inflammation inhibition activity, and pain relieving activity of the conjugates. The invention also finds that the conjugates do not have any side effect leading to osteoporosis. The researches on the inhibition effect of the conjugates on splenic lymphocyte mitogen proliferation reactions and the survival time after mouse retroauricular cardiac muscle transplant show that the conjugates have an excellent immunity inhibition effect. The researches on the effect of the conjugates on the swelling degree of mouse ears which are inflamed due to xylene show that the conjugates have an excellent anti-inflammation effect. The researches on the effect of the conjugates on mouse heat radiation tail flick time show that the conjugates have an excellent pain-relieving effect. The researches on the effect of the conjugates on the mouse thigh bones show that the conjugates cannot cause osteoporosis. So the conjugates have a wide application prospect in the preparation of immunity inhibition drugs.

Description

technical field [0001] The present invention relates to six saturated fatty chain alcohol modified dexamethasone-Glu-Asp-Gly conjugates represented by formula 10a-f, n=7, 9, 11, 13, 15, 17 in saturated fatty chain alcohol, It relates to their preparation methods, their nanostructures, their immunosuppressive, anti-inflammatory and analgesic activities, and their osteoporotic side effects. The present invention shows that they have excellent immunosuppressive effects through the inhibitory effect of 10a-f on the mitogen proliferation response of spleen lymphocytes and the survival time after transplantation of the myocardium behind the ear in mice, and studies the effect of 10a-f on xylene-induced effects on mice. Inflammatory ear swelling, indicating that they have excellent anti-inflammatory effects, studying the effects of 10a-f on the tail flick time of mice with thermal radiation, indicating that they have excellent analgesic effects, studying the effects of 10a-f on mouse...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/093A61K9/107A61K38/06A61P37/00A61P29/00A61P19/10A61K9/127A61P37/06
Inventor 彭师奇赵明吴建辉王玉记董翘巧
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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