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Polyaspartyl-K-estradiol as well as preparation, anti-osteoporosis activity and application thereof

A technology of polyaspartyl and estradiol, which is applied in the field of biomedicine and can solve the problems of no evaluation of activity and side effects

Active Publication Date: 2018-02-13
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, a patent (US 7,067,505 B2) disclosed in the United States in 2006 has involved the main chain of an aspartic acid and the carboxyl group of the side chain to connect two estradiol compounds (abbreviated as 1-aspartate 2-estradiol) Synthetic method, but no evaluation of its activity and side effects

Method used

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  • Polyaspartyl-K-estradiol as well as preparation, anti-osteoporosis activity and application thereof
  • Polyaspartyl-K-estradiol as well as preparation, anti-osteoporosis activity and application thereof
  • Polyaspartyl-K-estradiol as well as preparation, anti-osteoporosis activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1 Preparation of estradiol-3-O-ethyl acetate (1)

[0017] Dissolve 10.00g (36.76mmol) estradiol with acetone, then add 5.60g (40.58mmol) K 2 CO 3 And 4.5mL (40.42mmol) ethyl bromoacetate, reflux at 60°C for 12h, TLC (petroleum ether / ethyl acetate, 2 / 1) showed that estradiol disappeared. Filter to remove K 2 CO 3 Solid, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1) to obtain 7.80 g (59%) of the title compound as a colorless solid. ESI-MS(m / e):358.85[M+H] + ,739.93[2M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ): δ / ppm=7.16(d, J=8.4Hz, 1H), 6.65(dd, J 1 =8.4Hz,J 2 =2.7Hz,1H),6.58(d,J=2.7Hz,1H),4.68(s,2H),4.50(d,J=4.5Hz,1H),4.16(q,J=3.3Hz,2H), 3.52(m,1H),2.74(m,2H),2.26(d,J=13.5Hz,1H),2.11(m,1H),1.87-1.78(m,3H),1.53(m,1H),1.39 -1.21(m,10H),0.66(s,3H).

Embodiment 2

[0018] Example 2 Preparation of estradiol-3-O-acetic acid (2)

[0019] Dissolve 7.00 g (19.55 mmol) of estradiol-3-O-ethyl acetate in 150 mL of methanol under an ice bath, add NaOH aqueous solution (2M) to adjust the pH to 12, TLC (petroleum ether / ethyl acetate, 1 / 1, Addition of 2 drops of glacial acetic acid) showed disappearance of ethyl estradiol-3-O-acetate. The reaction mixture was washed with 5% KHSO 4 Adjust the pH of the aqueous solution to neutral, concentrate under reduced pressure to remove methanol, add 40 mL of distilled water to the residue, and use 5% KHSO 4 The aqueous solution was adjusted to pH 2, then extracted with ethyl acetate. Ethyl acetate layer with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to afford 5.89 g (91%) of the title compound as a colorless solid. ESI-MS(m / e):329.39[M-H] - ,659.69[2M-H] - ; 1 H-NMR (300MHz, DMSO-d 6 ):δ / ppm=12.95(s,1H),7.16(d,J=8.4Hz,1H),6.65(dd,J 1 =8.4Hz,J 2 =2.1Hz,1H),6....

Embodiment 3

[0020] Example 3 Preparation of N-estradiol-3-O-acetyl-Lys(Boc)-OBzl

[0021] Dissolve 3.60g (10.91mmol) estradiol-3-O-acetic acid in anhydrous tetrahydrofuran (THF) under ice bath, add 1.51g (11.19mmol) 1-hydroxybenzotriazole (HOBt) and 2.52g ( 12.23mmol) dicyclohexylcarbodiimide (DCC), activated for 0.5h. Dissolve 4.81g (13.26mmol) HCl Lys(Boc)-OBzl in anhydrous tetrahydrofuran, adjust the pH to 8 with N-methylmorpholine (NMM), add it to the activation solution just obtained, and then use NMM Adjust the pH of the reaction solution to be 8, remove the ice bath, react at room temperature for 8 hours, monitor the disappearance of estradiol-3-O-acetic acid on a TLC board (dichloromethane / methanol, 20 / 1), and filter the reaction solution to remove dicyclohexyl urea (DCU ), the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, the remaining DCU in the solution was removed by filtration, the ethyl acetate layer was washed 3 times with 5%...

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Abstract

The invention discloses polyaspartyl-lysyl-estradiol (polyaspartyl-K-estradiol, for short) containing 119 aspartic acid residues, as well as a preparation method and application thereof in resisting osteoporosis on a mouse osteoporosis model. The invention elaborates application of the polyaspartyl-K-estradiol in preparing an anti-osteoporosis medicine.

Description

technical field [0001] The present invention relates to polyaspartyl-lysyl-estradiol containing 119 aspartic acid residues (abbreviated as polyaspartate-K-estradiol), relates to its preparation method, and further relates to its production in mice Antiosteoporotic effects on osteoporotic models. Therefore, the present invention clarifies the application of polyaspartate-K-estradiol in the preparation of anti-osteoporosis drugs. The invention belongs to the field of biomedicine. Background technique [0002] Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural disruption of bone tissue, leading to increased bone fragility and susceptibility to fractures. Drug-induced osteoporosis commonly occurs in patients taking glucocorticoids in clinic. Glucocorticoids, such as cortisone, hydrocortisone, and dexamethasone, are first-line anti-inflammatory and immunosuppressive agents in clinical practice. Although glucocorticoids have good anti-infl...

Claims

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Application Information

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IPC IPC(8): C08G73/10A61K31/565A61P19/10
CPCA61K31/565C08G73/1003C08G73/1092
Inventor 彭师奇赵明王玉记吴建辉冯琦琦
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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