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Indole skeleton-containing dihydropyrazolpiperazine C21 steroid sapogenin derivative, and preparation method and application thereof

A technology of dihydropyrazolopiperazine and saponin aglycone, which can be used in medical preparations containing active ingredients, steroids, drug combinations, etc., and can solve problems such as poor water solubility and limited clinical application.

Inactive Publication Date: 2015-08-12
JIANGSU NAIQUE BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of these drugs have poor water solubility, which limits their clinical application as oral and injectable agents

Method used

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  • Indole skeleton-containing dihydropyrazolpiperazine C21 steroid sapogenin derivative, and preparation method and application thereof
  • Indole skeleton-containing dihydropyrazolpiperazine C21 steroid sapogenin derivative, and preparation method and application thereof
  • Indole skeleton-containing dihydropyrazolpiperazine C21 steroid sapogenin derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] N-methyl-4-(5-(3-indole)-3-((3aR,4aS,8S,10aS,11S,12S,12aS)-(8,11,12-trihydroxy)-(10a, 12a-Dimethyl)-(1,2-cyclopentyl)-1,10a-b-epoxy-n-tetradecyl)-(4,5-dihydropyrazole))benzoylpiperazine (Compound 26) Preparation

[0062]

[0063] Under stirring at -20°C, add the corresponding intermediate 21 (10.0mmol) and dichloromethane (25mL) obtained in step 7 to a 50mL round bottom flask in turn, and gradually add boron tribromide (5mmol) dropwise to continue the reaction with stirring After 1 h, the reaction flask was transferred to room temperature, and the reaction was continued for 12 h. TLC tracking reaction (developing agent V AcOEt :V 正己烷 =1:2), after the reaction was completed, filtered, the solid was washed with distilled water, and finally dried in vacuo, and the obtained solid was dissolved in absolute ethanol for recrystallization and purification to obtain the crystalline target compound.

[0064] White crystals were obtained with a yield of 47.1%. m.p.213~215℃...

Embodiment 2

[0066] N-methyl-4-(5-(3-(7-methyl-indole))-3-((3aR,4aS,8S,10aS,11S,12S,12aS)-(8,11,12- Trihydroxy)-(10a,12a-dimethyl)-(1,2-cyclopentyl)-1,10a-b-epoxytetradecyl)-(4,5-dihydropyrazole )) Preparation of Benzoylpiperazine (Compound 27)

[0067]

[0068] The preparation method is the same as in Example 1. White crystals were obtained with a yield of 45.3%. m.p.225~226℃; 1 H NMR (DMSO-d 6,300MHz)δ:10.79(s,1H,NH),8.00(d,J=8.4Hz,2H,ArH),7.72(d,J=6.9Hz,2H,ArH),7.48(d,J=5.8Hz ,1H,ArH),7.21(d,J=5.5Hz,1H,ArH),7.18(s,1H,CH),7.06(t,J=7.3Hz,1H,CH),5.35(s,2H,OH ), 5.19(t, J=7.3Hz, 1H, CH), 4.49(s, 1H, OH), 3.54(dd, J 1 =4.7,J 2 =4.8Hz,1H,CH),3.47~3.36(m,6H,CH and CH 2 ),3.32~3.13(m,2H,CH 2 ),2.68(s,3H,CH 3 ), 2.33(t, J=5.8Hz, 4H, CH 2 ),2.18(s,3H,CH 3 ), 2.01(t, J=7.1Hz, 1H, CH), 1.74~1.21(m, 15H, CH and CH 2 ),1.14(dd,J 1 =7.2Hz,J 2 =7.1Hz,1H,CH),0.89(s,3H,CH 3 ),0.84(s,3H,CH 3 ).ESI-MS:722.9[M+H] + .Anal.Calcd for C 43 h 55 N 5 o 5 :C,H,N.

Embodiment 3

[0070] N-methyl-4-(5-(3-(6-methyl-indole))-3-((3aR,4aS,8S,10aS,11S,12S,12aS)-(8,11,12- Trihydroxy)-(10a,12a-dimethyl)-(1,2-cyclopentyl)-1,10a-b-epoxytetradecyl)-(4,5-dihydropyrazole )) Preparation of Benzoylpiperazine (Compound 28)

[0071]

[0072] The preparation method is the same as in Example 1. White crystals were obtained with a yield of 42.3%. m.p.217~218℃; 1 H NMR (DMSO-d 6 ,300MHz)δ:10.78(s,1H,NH),7.93(dd,J 1 =7.1,J 2 =7.3Hz,4H,ArH),7.55(d,J=5.8Hz,1H,ArH),7.21(d,J=5.5Hz,1H,ArH),7.18(s,1H,CH),7.06(s, 1H,ArH),5.37(s,2H,OH),5.19(t,J=7.3Hz,1H,CH),4.49(s,1H,OH),3.54(dd,J 1 =4.7,J 2 =4.8Hz,1H,CH),3.47~3.08(m,8H,CH and CH 2 ),2.44(s,3H,CH 3 ),2.35(t,J=4.9Hz,4H,CH 2 ),2.20(s,3H,CH 3 ), 2.01(t, J=7.1Hz, 1H, CH), 1.79~1.21(m, 15H, CH and CH 2 ),1.14(dd,J 1 =7.2Hz,J 2 =7.1Hz,1H,CH),0.88(s,3H,CH 3 ),0.85(s,3H,CH 3 ).ESI-MS:722.9[M+H] + .Anal.Calcd for C 43 h 55 N 5 o 5 :C,H,N.

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Abstract

The invention discloses an indole skeleton-containing dihydropyrazolpiperazine C21 steroid sapogenin derivative, and a preparation method and an application thereof. A target compound represented by formula VIII is obtained through structural modification research by using a compound with a C21 steroid saponin parent nucleus as an initial compound. Pharmacological research results show that the compound has an obvious inhibition effect on human breast cancer cells, cervical carcinoma cells, lung cancer cells and liver cancer cells. In formula IV to the formula VIII, R1 is H or CH3, R2 is H or CH3, R3 is H or F, and R4 is H or CH3.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a dihydropyrazole-piperazine C containing an indole skeleton 21 Steroidal saponin aglycon derivatives, and preparation methods and applications thereof. Background technique [0002] Indole compounds are an important class of heterocyclic derivative alkaloids, and their cancer therapeutic effect has been widely concerned. Its representative indole compounds, vinblastine, indomethacin, melatonin, indole Yuhong, etc., all have good anti-tumor activities in different aspects. [0003] Piperazine, also known as hexahydropyrazine, is a six-membered heterocyclic ring containing 2 nitrogen atoms in the molecule. It has high formation enthalpy and good thermal stability. It is an ideal structural unit of nitrogen-rich heterocyclic compounds and is an important component of many drugs. component. Compared with traditional organic drugs, piperazine compounds have a better nitrogen balance ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61K31/58A61P35/00
CPCC07J71/0021
Inventor 金显友杨永安钟慧魏元刚
Owner JIANGSU NAIQUE BIOLOGICAL ENG
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