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2h-pyrazole sulfanilamide steroid saponin aglycone derivative containing indole framework and preparation method and application thereof

A dihydropyrazole sulfonamide steroid and saponin aglycon technology, which is applied in the field of dihydropyrazole sulfonamide steroid aglycone derivatives, can solve the problems of low biological activity and selectivity and high toxicity, and achieve a mild experimental environment, Low toxicity, good stability

Active Publication Date: 2015-07-15
JIANGSU NAIQUE BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the existing products still have disadvantages such as low biological activity and selectivity, and high toxicity.

Method used

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  • 2h-pyrazole sulfanilamide steroid saponin aglycone derivative containing indole framework and preparation method and application thereof
  • 2h-pyrazole sulfanilamide steroid saponin aglycone derivative containing indole framework and preparation method and application thereof
  • 2h-pyrazole sulfanilamide steroid saponin aglycone derivative containing indole framework and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] 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 tetradecyl)-(4,5-dihydropyrazole))benzenesulfonamide (compound 24)

[0055]

[0056] Under stirring at -20°C, add the corresponding intermediate 14 (10.0mmol) and dichloromethane (25mL) obtained in step 4 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.

[0057] White crystals were obtained with a yield of 47.7%. m.p.224~225℃; 1 H NMR (DMSO-d 6 ,...

Embodiment 2

[0059] 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-epoxy-n-tetradecyl)-(4,5-dihydropyrazole))benzenesulfonamide (Compound 25) Preparation

[0060]

[0061] The preparation method refers to Example 1. White crystals were obtained with a yield of 45.3%. m.p.224~226℃; 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),6.89(s,2H,NH 2 ),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), 3.44(t, J=8.1Hz, 1H, CH), 3.36(d, J=6.8Hz, 1H, CH), 3.32~3.13(m, 2H, CH 2 ),2.68(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:675.9[M+H] + .Anal.Calcd for C 37 h 46 N 4 o 6 S: C, H, N.

Embodiment 3

[0063] 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-epoxy-n-tetradecyl)-(4,5-dihydropyrazole))benzenesulfonamide (Compound 26) Preparation

[0064]

[0065] The preparation method refers to Example 1. White crystals were obtained with a yield of 42.3%. m.p.212~214℃; 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),6.89(s,2H,NH 2 ),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), 3.44(t, J=8.1Hz, 1H, CH), 3.36(d, J=6.8Hz, 1H, CH), 3.34~3.01(m, 2H, CH 2 ),2.44(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),0.89(s,3H,CH 3 ),0.84(s,3H,CH 3 ).ESI-MS:675.9[M+H] + .Anal.Calcd for C 37 h 46 N 4 o 6 S: C, H, N.

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Abstract

The invention discloses a 2h-pyrazole sulfanilamide steroid saponin aglycone derivative containing indole framework and a preparation method and application thereof. The structure of the 2h-pyrazole sulfanilamide steroid saponin aglycone derivative containing the indole framework is shown as the formula VII in the specification. R1 is selected from H, CH3 and CH2CH3. R2 is selected from H, CH3, CH2CH3, F, C1 and Br. R3 is selected from H and CH3. R4 is selected from H and CH3. The 2h-pyrazole sulfanilamide steroid saponin aglycone derivative has a remarkable restraint effect on breast cancer cells (MCF-7), cervical cancer cells (HeLa), lung cancer cells (A549) and hepatoma cancer cells (HepG2) of human body, has identical or superior cell toxicity to human renal epithelial cells (293T) compared with a positive reference drug (Celecoxib), has better biological cavity, higher selectivity and lower toxicity, and can be used for preparing anti-cancer drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a dihydropyrazole sulfonamide steroidal saponin aglycone derivative containing an indole skeleton, a preparation method and application thereof. Background technique [0002] C21 steroidal saponin is a steroidal saponin component obtained through extraction, separation and purification from the traditional Chinese medicine Tongguanteng. Its aglycone is a unique steroidal saponin structure composed of 21 C atoms, so it is called C21 steroidal saponin. Compounds with a C21 steroidal saponin core have pharmacological activities such as immune regulation and antiasthma, and have been widely used clinically as index active ingredients of drugs. [0003] After in-depth research by the applicant, it is found that the compound with C21 steroidal saponin core may have good anti-tumor activity. The current research content on this type of C21 steroidal saponins mainly includes: separati...

Claims

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Application Information

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IPC IPC(8): C07J71/00A61K31/58A61P35/00
CPCC07J71/001
Inventor 严晓强朱海亮杨永安钟飞俞海荣
Owner JIANGSU NAIQUE BIOLOGICAL ENG
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