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Alpha-naphthalenesulfonamide base quintuple heterocyclic compound and anti-tumor activity thereof

A technology of naphthalenesulfonamide and five-membered heterocycles, applied in the field of α-naphthalenesulfonamide five-membered heterocycles

Inactive Publication Date: 2012-04-25
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The α-naphthalenesulfonamido five-membered heterocyclic compound of the present invention and its new application in anti-tumor aspect have not yet seen relevant reports at home and abroad

Method used

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  • Alpha-naphthalenesulfonamide base quintuple heterocyclic compound and anti-tumor activity thereof
  • Alpha-naphthalenesulfonamide base quintuple heterocyclic compound and anti-tumor activity thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] N-{5-[(N-n-butylamino)formyl]-4,6-dihydro-1H-pyrrole[3,4-c]pyrazol-3-yl}-5- Chloronaphthalene-1-sulfonamide

[0063] (a) Preparation of 3-amino-4,6-dihydro-1H-pyrrole[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester

[0064] N 2 Under protection, 9.0 g of 1-tert-butoxycarbonyl-3-cyano-4-pyrrolidone, 0.043 mol (see Daniele Fancelli, et al. J. Med. Chem. 2005, 48, 3080-3084 for the synthesis method), hydrochloric acid The mixture of hydrazine (4.5g, 0.0428mol) and ethanol (250mL) was stirred and reacted at 60°C for 3h, then cooled to 0°C and slowly added 600mL of saturated aqueous sodium bicarbonate solution dropwise, and after stirring for 30min, the resulting reaction solution was spun under reduced pressure Most of the ethanol and water were evaporated, the remaining liquid was extracted with ethyl acetate (300mL), the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to remove the solvent to obtain a ligh...

Embodiment 2

[0086] N-{5-[(N-n-butylamino)formyl]-4,6-dihydro-1H-pyrrole[3,4-c]pyrazol-3-yl}-naphthalene- 1-sulfonamide

[0087] (a) Preparation of N-{5-tert-butoxycarbonyl-4,6-dihydro-1-ethoxycarbonylpyrrole[3,4-c]pyrazol-3-yl}-naphthalene-1-sulfonamide

[0088] According to the method of step (c) of Example 1, the product of step (b) of Example 1 was reacted with 1-naphthalenesulfonyl chloride to obtain the subtitle compound as a white powder with a yield of 69%.

[0089] MS (ESI, m / z): 487 (M + +1, 100%).

[0090] (b) Preparation of N-{4,5,6-trihydro-1-ethoxycarbonylpyrrole[3,4-c]pyrazol-3-yl}-naphthalene-1-sulfonamide hydrochloride

[0091] Prepared according to the method of step (d) of Example 1, using the product of step (a) of Example 2 to obtain the subtitle compound in the form of white powder with a yield of 100%.

[0092] MS (ESI, m / z): 387 (M + +1, 100%).

[0093] (c) N-{5-[(N-n-butylamino)formyl]-4,6-dihydro-1-ethoxycarbonylpyrrole[3,4-c]pyrazol-3-yl}-naphthalene - Pr...

Embodiment 3

[0099] N-{5-[(N-n-butylamino)formyl]-4,6-dihydro-1H-pyrrole[3,4-c]pyrazol-3-yl}-5- Iodonaphthalene-1-sulfonamide

[0100] (a) N-{5-tert-butoxycarbonyl-4,6-dihydro-1-ethoxycarbonylpyrrole[3,4-c]pyrazol-3-yl}-5-iodonaphthalene-1-sulfonamide preparation of

[0101] According to the method of step (c) of Example 1, the product of step (b) of Example 1 was reacted with 5-iodo-1-naphthalenesulfonyl chloride to obtain the subtitle compound as a white powder with a yield of 50%.

[0102] MS (ESI, m / z): 613.3 (M + +1, 100%).

[0103] (b) Preparation of N-{4,5,6-trihydro-1-ethoxycarbonylpyrrole[3,4-c]pyrazol-3-yl}-5-iodonaphthalene-1-sulfonamide hydrochloride

[0104] Prepared according to the method of step (d) of Example 1, using the product of step (a) of Example 3 to obtain the subtitle compound in the form of white powder with a yield of 100%.

[0105] MS (ESI, m / z): 513.2 (M + +1, 100%).

[0106] (c) N-{5-[(N-n-butylamino)formyl]-4,6-dihydro-1-ethoxycarbonylpyrrole[3,4-c]p...

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Abstract

The invention relates to an alpha-naphthalenesulfonamide base quintuple heterocyclic compound and application thereof in anti-tumor treatment. Shown as research results, the alpha-naphthalenesulfonamide base quintuple heterocyclic compound, an isomer thereof, a stereomer or a mixture of the stereomer and a pharmaceutically acceptable salt or a precursor all have suppression effects on tumor cells, wherein the suppression ratios of about half compounds on the cell level are superior to that of ML-7 positive control medicine. The invention is expected to lay the foundation for developing anti-tumor medicaments.

Description

Technical field: [0001] The invention relates to α-naphthalene sulfonamide five-membered heterocyclic compounds and their application in antitumor therapy. Background technique: [0002] In 2003, U.S. Patent (US20030171357A1) disclosed a series of 3-aminopyrazole compounds that can be used as protein kinase inhibitors, especially related documents [P.Pevarello, et al.J.Med.Chem.2004, 47 (13) , 3367-3380]; P.Pevarello, et al.Bioorg.Med.Chem.Lett.2006, 16, 1084-1090; Daniele Fancelli, et al.J.Med.Chem.2005, 48, 3080-3084] It was found that as a CDK2 inhibitor, it can effectively inhibit the malignant growth of tumor cells, and has good selectivity for CDK2. Cyclin-dependent kinase (CDK) is a serine / threonine protein kinase, which determines whether the cell cycle proceeds in an orderly manner, and it is only active when combined with the corresponding cell cycle protein. There are seven main CDKs (CDK1-7), the content of which is basically stable throughout the cell cycle. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D498/04C07D471/04A61K31/4162A61K31/42A61K31/437A61P35/00
Inventor 王玉成白晓光邵荣光王菊仙郭欣李祎亮任开环
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI