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Beta-elemene macrocyclic derivative as well as preparation method and application thereof

A technology of macrocyclic derivatives and elemene, which is applied in the direction of drug combination, pharmaceutical formulation, bulk chemical production, etc., can solve the problems of poor water solubility, low polarity of elemene, and low bioavailability of oral administration

Active Publication Date: 2021-11-26
HANGZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, due to the low polarity, poor water solubility and low oral bioavailability of elemene, its clinical application is limited.

Method used

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  • Beta-elemene macrocyclic derivative as well as preparation method and application thereof
  • Beta-elemene macrocyclic derivative as well as preparation method and application thereof
  • Beta-elemene macrocyclic derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1: the preparation of compound 1

[0084]

[0085] At room temperature, add 1b (536mg, 3.84mmol) to compound 1a (1042mg, 3.84mmol) in anhydrous N,N-dimethylformamide (DMF) (8mL) solution, after stirring and clarification, add N,N-diisopropylethylamine (DIPEA) (1092mg, 8.45mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluoro Phosphate (HATU) (1460 mg, 3.84 mmol), stirred overnight. DMF was distilled off under reduced pressure, ice water (40 mL) was added to quench the reaction, and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed successively with water (10 mL x 2) and saturated brine (10 mL x 2), and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluted with ethyl acetate / petroleum ether / triethylamine (0.1%) system) to obtain yellow oil...

Embodiment 2

[0091] Embodiment 2: the preparation of compound 2

[0092]

[0093] Referring to the synthesis method of Example 1, compound 2f (252 mg, yield 46%) was obtained. 1 H NMR (500MHz, CDCl 3 )δ6.13(t,J=4.9Hz,1H),5.79(dd,J=17.5,10.8Hz,1H),5.00(s,1H),4.95–4.81(m,4H),4.74(s,1H ),3.68(s,3H),3.50(q,J=6.1Hz,2H),3.39(s,4H),2.97(d,J=13.9Hz,1H),2.90(q,J=13.3Hz,2H ),2.81–2.71(m,2H),2.59(d,J=13.9Hz,1H),2.53(t,J=6.0Hz,2H),2.31(s,4H),2.20(dd,J=12.7, 3.1Hz, 1H), 2.14–2.09(m, 2H), 2.07(d, J=12.1Hz, 1H), 1.89(t, J=11.3Hz, 1H), 1.56(dq, J=42.1, 13.9, 13.0 Hz,9H),1.44(s,9H),1.40(d,J=12.7Hz,1H),1.30–1.05(m,6H),0.98(s,3H).LCMS m / z643.0[M+H ] + .

[0094] Referring to the synthesis method of Example 1, compound 2f (245 mg, 0.38 mmol) was subjected to Boc deprotection, ester hydrolysis, and amide condensation in sequence to finally obtain white solid compound 2 (97 mg, yield 76%). 1 H NMR (400MHz, CDCl 3 )δ6.30–6.20(m,1H),5.76(dd,J=17.5,10.8Hz,1H),4.93–4.87(m,3H),4.86(d,J=1.2Hz,1H),4.84–4.82...

Embodiment 3

[0095] Embodiment 3: the preparation of compound 3

[0096]

[0097] Referring to the synthesis method of Example 1, compound 3c (1602 mg, yield 85%) was obtained in the first step. 1 H NMR (500MHz, CDCl 3 )δ5.59(s,1H),3.65(s,3H),3.24(q,J=7.0Hz,2H),2.72(t,J=11.0Hz,2H),2.30(t,J=7.4Hz, 2H), 2.19(tt, J=11.6, 3.7Hz, 1H), 1.78(d, J=12.6Hz, 2H), 1.66–1.58(m, 4H), 1.50(dt, J=14.8, 7.4Hz, 3H ), 1.44(s,9H), 1.39–1.28(m,3H).

[0098] The second step produced the hydrochloride (763mg, 2.61mmol) of compound 3d, LCMS m / z 257.2[M+H] + . The crude product was directly used in the next reaction without purification.

[0099] The third step yielded compound 3f (142 mg, yield 66%). 1 H NMR (500MHz, CDCl 3 )δ5.80(dd, J=17.5,10.8Hz,1H),5.58(t,J=5.1Hz,1H),5.01(s,1H),4.92(d,J=7.3Hz,2H),4.90– 4.81(m,2H),4.75(s,1H),3.65(s,3H),3.40(t,J=5.1Hz,4H),3.24(q,J=6.7Hz,2H),3.02(d,J =13.8Hz,1H),2.96–2.87(m,2H),2.87–2.78(m,2H),2.61(d,J=13.9Hz,1H),2.38–2.25(m,6H),2.21(dd, J=12.9, 3.2Hz, 1H), 2.11–1.9...

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Abstract

The invention discloses beta-elemene macrocyclic derivatives as well as a preparation method and application thereof in preparation of antitumor drugs. The structure of the beta-elemene macrocyclic derivative is as shown in any one of formulas (I)-(III).

Description

technical field [0001] The invention relates to the technical field of preparation of beta-elemene derivatives, in particular to beta-elemene macrocyclic derivatives and their preparation methods and applications. Background technique [0002] Elemene is a kind of small molecule volatile oil compound, which is mainly extracted from the tuber of curcuma. The elemene reported in the current literature mainly includes α-elemene, (±)-β-elemene, γ-elemene and δ-elemene, wherein (-)-β-elemene is Its main active ingredient that exerts anti-tumor effect has broad-spectrum anti-tumor activity, and has certain curative effects on various cancers, such as liver cancer, breast cancer, and lung cancer. At present, a variety of preparations with elemene as the main component have achieved certain anticancer effects in clinical practice. [0003] However, due to the low polarity, poor water solubility and low oral bioavailability of elemene, its clinical application is limited. Therefor...

Claims

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Application Information

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IPC IPC(8): C07D471/08C07D471/18C07D471/22C07D487/18C07D245/04C07D257/10C07D255/04C07D498/18C07D273/02A61K31/439A61K31/4995A61K31/395A61P35/00
CPCC07D471/08C07D471/18C07D471/22C07D487/18C07D245/04C07D257/10C07D255/04C07D498/18C07D273/02A61P35/00Y02P20/55
Inventor 谢恬戚香卓晓韬高园白仁仁叶向阳
Owner HANGZHOU NORMAL UNIVERSITY
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