Amino-substituted rutaecarpin analog, and synthesis method and application thereof in preparation of anti-obesity medicaments

A technology of evodiamine and its analogues, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve problems such as poor water solubility, poor oral absorption, and limited application prospects, and achieve the effect of inhibiting lipogenesis and reducing fat accumulation

Active Publication Date: 2012-11-14
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the compound has poor water solubility, and its solubility in water is only 0.05±0.02 μg / m, resulting in poor oral absorption and low bioavailability, which will limit its application prospects in obesity treatment

Method used

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  • Amino-substituted rutaecarpin analog, and synthesis method and application thereof in preparation of anti-obesity medicaments
  • Amino-substituted rutaecarpin analog, and synthesis method and application thereof in preparation of anti-obesity medicaments
  • Amino-substituted rutaecarpin analog, and synthesis method and application thereof in preparation of anti-obesity medicaments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Synthesis of compound 2

[0032] Add 0.01mol anthranilamide to 10 ml of triethyl orthopropionate, heat and reflux at 155°C for 12h, then cool to 0°C and let stand for 1-2h, carefully filter the crystals, wash with a small amount of ethanol, and dry in vacuo Afterwards, white needle-like crystals 2 were obtained.

[0033] Yield: 71%; 1 H-NMR (400 MHz, DMSO)δ(ppm): 12.12 (s, 1H), 8.08 (dd, J = 7.9, 1.4, 1H), 7.83–7.73 (m, 1H), 7.60 (d, J = 8.1 , 1H), 7.51–7.41 (m, 1H), 2.62 (q, J = 7.5, 2H), 1.25 (t, J = 7.5, 3H); ESI-MS m / z: 175 [M+H] + .

[0034]

[0035] Compound 2.

Embodiment 2

[0036] Example 2: Synthesis of compound 3

[0037]Dissolve 0.01mol of compound 2 and 0.01mol of sodium acetate in 120ml of acetic acid, heat to 60°C, and slowly add 0.01mol of liquid Br 2 10ml of acetic acid solution. After the dropwise addition, the reaction solution continued to stir until the liquid Br in the reaction solution 2 The brown color disappeared (about 3h), and the reaction solution was poured into 300ml of ice water, resulting in a large amount of white precipitate, which was collected by filtration and vacuum-dried to obtain a white solid 3.

[0038] Yield: 69%; 1 H-NMR (400 MHz, DMSO)δ(ppm): 12.46 (s, 1H), 8.16 – 8.09 (m, 1H), 7.87–7.80 (m, 1H), 7.69 (d, J = 8.1, 1H), 7.55 (t, J = 7.5, 1H), 5.10 (q, J = 6.8, 1H), 2.01 (d, J = 6.8, 3H); ESI-MS m / z: 253 [M+H] + .

[0039]

[0040] Compound 3.

Embodiment 3

[0041] Embodiment 3: Synthesis of Compound 4

[0042] Dissolve 0.01 mol of compound 3 and 0.04 mol of phenylhydrazine in 80 ml of ethanol, heat and reflux for 10 h, after cooling the reaction solution produces a large amount of orange cotton-like solid, filter the precipitate, wash with a small amount of ethanol and dry, then recrystallize with ethanol An orange solid 4 was obtained.

[0043] Yield: 82%; 1 H-NMR (400 MHz, DMSO) δ (ppm): 1H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 9.86 (s, 1H), 8.13 (dd, J = 7.9, 1.1, 1H), 7.85–7.76 (m, 1H), 7.67 (d, J = 8.1, 1H), 7.58 (d, J = 8.2, 2H), 7.48 (t, J = 7.5, 1H), 7.28 (t, J = 7.8, 2H), 6.89 (t, J = 7.3, 1H), 2.35 (s, 3H); ESI-MS m / z: 279 [M+H] + .

[0044]

[0045] Compound 4.

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Abstract

The invention relates to the fields of pharmaceutical chemistry and pharmaceutical therapeutics, and provides an amino-substituted rutaecarpin analog, and a synthesis method and application thereof in the preparation of anti-obesity medicaments. Experiments prove that the amino-substituted rutaecarpin analog provided by the invention can obviously reduce the lipopexia of 3T3-L1 fat cells, and can reduce the high levulose-induced lipopexia of FAO rat liver cells. Cellular level tests show that the compound can reduce lipopexia and has an effect of relieving obesity and alleviating fatty liver. The chemical formula of the amino-substituted rutaecarpin analog is shown in the specification. In the chemical formula, R0 is -NH(CH2)nR2, n is 1, 2, 3, 4 or 5, and R2 is -N(CH3)2, -N(CH2CH3)2, cyclopentylamino or cyclohexylamino; or R0 is morpholinyl, piperazinyl or methylpiperazinyl.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to amino-substituted evodiamine analogues, their synthesis methods and their application in the preparation of anti-obesity medicines. Background technique [0002] Obesity is a clinical metabolic disease caused by long-term energy intake and energy expenditure imbalance caused by excess body energy and low activity. The World Health Organization stipulates: body mass index (BMI is the square of weight divided by height) ≥ 30kg / m 2 is obese. Obesity is an important cause of type 2 diabetes and cardiovascular disease. Therefore, obesity and its complications have become a worldwide public health problem that seriously threatens human health and quality of life. [0003] Due to changes in lifestyle and diet structure, the number of obese patients has increased year by year in recent years. According to the World Health Organization's assessment results ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/14A61K31/519A61K31/5377A61P3/04
CPCC07D487/14A61K31/519A61P3/04
Inventor 黄志纾叶冀明陈迎春贺彦谭嘉恒曾晓毅古练权
Owner SUN YAT SEN UNIV
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