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Sesquiterpene derivative as well as pharmaceutical composition, preparation method and application thereof

A derivative and composition technology, applied in the field of medicinal chemistry, can solve the problems of difficult to maintain long-term drug concentration, fast prodrug release, short half-life, etc., and achieve the effects of stable drug release time, long half-life and stable structure.

Pending Publication Date: 2022-07-12
TIANJIN JIKUN MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the analogs of alkanediamines such as dimethylamine and diethylamine are modified, and the resulting prodrugs are released too fast in plasma and have a short half-life, making it difficult to maintain a long-term drug concentration.

Method used

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  • Sesquiterpene derivative as well as pharmaceutical composition, preparation method and application thereof
  • Sesquiterpene derivative as well as pharmaceutical composition, preparation method and application thereof
  • Sesquiterpene derivative as well as pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation of Compound 1

[0042] The structure of compound 1 is as follows:

[0043]

[0044] Its preparation process is as follows:

[0045] At 0°C, selenium dioxide (2.86 g, 25.8 mmol) was dissolved in dichloromethane (250 mL), tert-butanol peroxide (15.5 mL) was added, and after stirring for 30 minutes, isoinulin (30 g) was added. , 0.129mol) dichloromethane (250mL) solution was slowly added to the above system, stirred at room temperature for 8 hours, and then quenched the reaction with saturated aqueous sodium thiosulfate solution (500mL), after separation, the aqueous phase was mixed with dichloromethane Methane extraction (300 mL×3), the organic phases were combined, dried, concentrated, and recrystallized with petroleum ether / ethyl acetate mixed solvent to obtain Intermediate 1 (white solid, 19.5 g, yield 61%), which was then directly used with in the next step.

[0046] At 0 °C, compound intermediate 1 (19.5 g, 78.5 mmol) was dissolved in dic...

Embodiment 2

[0051] Example 2: Fumarate salt of compound 1 - preparation of compound 5

[0052] The structure of compound 5 is as follows:

[0053]

[0054] Compound 1 (998 mg, 2.84 mmol) prepared in Example 1 was dissolved in tetrahydrofuran (20 mL), and after stirring uniformly, fumaric acid (313 mg, 2.70 mmol) was added to the system, and the reaction was stirred at room temperature for 3 hours. After completion, the tetrahydrofuran was removed by concentration under reduced pressure, then ethyl acetate (100 mL) was added to the reaction system to obtain a suspension, which was filtered with suction to obtain compound 5 (white solid, 815 mg, yield 61%).

[0055] Compound 5 was detected, and its NMR data were as follows:

[0056] 1 H NMR(400MHz, DMSO)δ6.62(s,2H),4.48(d,J=4.2Hz,1H),3.56(t,J=4.7Hz,4H),3.16(dd,J=10.7,4.7Hz ,2H),2.75(d,J=4.5Hz,1H),2.47–2.35(m,6H),2.28(dt,J=10.7,4.5Hz,2H),2.09(dd,J=13.0,2.4Hz, 1H), 1.96 (d, J=15.3Hz, 1H), 1.80–1.65 (m, 1H), 1.63–1.42 (m, 3H), 1.35–1.24...

Embodiment 3

[0057] Example 3: Preparation of Compound 2

[0058] The structure of compound 2 is as follows:

[0059]

[0060] Its preparation process is as follows:

[0061] Using N-methylpiperazine (1.89 g, 18.9 mmol), following the synthetic procedure of compound 1 in Example 1, the target compound 2 (white solid, 993 mg, yield 72%) was obtained.

[0062] Compound 2 was detected, and its NMR data were as follows:

[0063] 1 H NMR(400MHz, DMSO)δ4.47(s,1H),3.17(d,J=2.7Hz,1H),3.13(td,J=6.2,3.1Hz,1H),2.75(d,J=4.5Hz) ,1H),2.60(s,4H),2.57–2.51(m,2H),2.51(d,J=1.8Hz,1H),2.49–2.45(m,2H),2.41(dd,J=12.9,4.5 Hz, 2H), 2.36(s, 1H), 2.34(s, 4H), 2.07(dd, J=12.9, 2.3Hz, 1H), 1.95(dd, J=15.5, 1.9Hz, 1H), 1.71(dt , J=15.0, 3.8Hz, 1H), 1.60–1.52 (m, 2H), 1.48 (dd, J=15.5, 4.3Hz, 1H), 1.32–1.24 (m, 1H), 1.19 (dd, J=12.4 ,3.2Hz,1H),0.83(s,3H),0.69–0.59(m,1H). 13 C NMR(100MHz, DMSO)δ177.5,77.5,71.1,60.9,53.7,52.5,48.0,44.3,44.1,41.3,38.4,36.8,34.7,34.3,27.7,18.0,15.5.HRMS(ESI):m / zcalcd for C 20 ...

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Abstract

The invention discloses a sesquiterpene derivative, and a pharmaceutical composition, a preparation method and application thereof. The invention relates to a sesquiterpenoid derivative shown in a formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the sesquiterpenoid derivative, and a preparation method and application of the sesquiterpenoid derivative. The sesquiterpenoid derivative or the pharmaceutically acceptable salt thereof has a stable structure, a long half-life period and a slow plasma clearance rate, shows long-acting and stable drug release time, shows excellent anti-tumor activity, can be used as a candidate of a long-acting anti-tumor drug, and has wide application prospects. The potential clinical application value and the wide clinical application prospect are realized.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a sesquiterpene derivative, a pharmaceutical composition thereof, and a preparation method and application thereof. Background technique [0002] In the past few decades, the morbidity and mortality of malignant tumors in the world have increased year by year, and malignant tumors have become the main cause of human death. At present, the main treatment methods for malignant tumors are surgery, radiation therapy and chemotherapy. However, at present, most malignant tumors still lack effective treatment methods, and the clinical therapeutic effect on malignant tumors is not ideal. Moreover, traditional anti-tumor drugs hinder their further clinical application due to the disadvantages of large toxic and side effects. At the same time, the rapid development of small molecule drugs provides new options for the treatment of malignant tumors, which have gradually become a research ...

Claims

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Application Information

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IPC IPC(8): C07D493/10A61P35/00A61K31/5377A61K31/496A61K31/4525A61K31/4025
CPCC07D493/10A61P35/00Y02P20/55
Inventor 杨诚杨光周红刚
Owner TIANJIN JIKUN MEDICAL TECH CO LTD
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