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Gamma-carbolines derivates as well as preparation method and application thereof

A carboline and product technology, applied in the field of synthesis of organic compounds, can solve the problems of complex structure, limited sources, and difficult synthesis, and achieve the effects of mild reaction conditions, reasonable design, and wide sources

Inactive Publication Date: 2009-05-06
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the development of microtubule-targeting agents has been very successful, paclitaxel and vinblastine compounds that act on tubulin have been widely used in clinical treatment of various tumors, however, these tubulin inhibitors often have the following problems: as structurally complex Natural product, its source is limited, and its synthesis is difficult; it will affect normal cells and has neurotoxicity; the existence of multi-drug resistance glycoprotein (P-gp) makes it lack long-term effect

Method used

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  • Gamma-carbolines derivates as well as preparation method and application thereof
  • Gamma-carbolines derivates as well as preparation method and application thereof
  • Gamma-carbolines derivates as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation of embodiment 1,9-ethyl-6-(4-bromobenzenesulfonamido)-γ-carboline (compound Ia1)

[0038]Dissolve homemade 6-amino-9-ethylγ-carboline (53mg, 0.25mmol) in DMF (1mL), add homemade 4-bromobenzenesulfonyl chloride (Su Yanxi et al., "Chemical World" , 2001, 12, 657-658) (64 mg, 0.25 mmol) and pyridine (81 μL, 1 mmol), and stirring was continued for 0.5 hours. The reaction solution was poured into water, extracted with ethyl acetate (5 mL×3), washed with saturated sodium chloride solution (5 mL×2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was recovered under reduced pressure to obtain a yellow solid, which was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: ethanol = 10:10:1) to obtain a white solid (compound Ia1), with a yield of 56%. Melting point: 154-156°C.

[0039] 1 H-NMR (δ, DMSO-d 6 ): 9.24(s, 1H), 8.57(d, 1H, J=6.4Hz), 8.04(s, 1H), 7.86(d, 1H, J=6.4Hz), 7.62(d, 2H, J=8.8Hz ), 7...

Embodiment 2

[0040] The preparation of embodiment 2,9-ethyl-6-(4-fluorobenzenesulfonamido)-γ-carboline (compound Ia2)

[0041] The operation process is the same as in Example 1, except that 4-bromobenzenesulfonyl chloride is replaced with 4-fluorobenzenesulfonyl chloride. A white solid (compound Ia2) was obtained in a yield of 52%. Melting point: 178-180°C.

[0042] 1 H-NMR (δ, DMSO-d 6 ): 10.18(brs, 1H), 9.28(s, 1H), 8.47(d, 1H, J=5.2Hz), 7.95(s, 1H), 7.78-7.76(m, 2H), 7.63-7.57(m, 2H), 7.37(t, 2H, J=8.8Hz), 7.18(d, 1H, J=8.4Hz), 4.41(q, 2H, J=6.8Hz), 1.29(t, 3H, J=6.8Hz) .

Embodiment 3

[0043] The preparation of embodiment 3,9-ethyl-6-(3-nitrobenzenesulfonamido)-γ-carboline (compound Ia3)

[0044] The operation process is the same as in Example 1, except that 4-bromobenzenesulfonyl chloride is replaced by self-made 3-nitrobenzenesulfonyl chloride (Ma Ying et al., CNZL200610052268.5, 2006). A white solid (compound Ia3) was obtained in a yield of 44%. Melting point: 159-161°C.

[0045] 1 H-NMR (δ, DMSO-d 6 ): 10.46 (brs, 1H), 9.33 (s, 1H), 8.49 (d, 2H, J=1.2Hz), 8.44 (dd, 1H, J=1.2, 8, 8Hz), 8.08 (d, 1H, J =8.8Hz), 8.00(d, 1H, J=2.0Hz), 7.82(t, 1H, J=8.8Hz), 7.65(d, 1H, J=6.0Hz), 7.62(d, 1H, J=8.8 Hz), 7.21(dd, 1H, J=8.8, 2, 0Hz), 4.43(q, 2H, J=7.2Hz), 1.29(t, 3H, J=7.2Hz).

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Abstract

The invention provides a gamma-carboline derivative, which is obtained by using gamma-carboline with antineoplastic activity as a lead compound, and introducing different lateral chains, aromatic rings, aromatic heterocycles or heterocycles to the sixth position of the gamma-carboline. Pharmacological active screening test shows that the compound has in-vitro antihyperplasia function on tumor cells; partial compound has obvious anti-tumor activity; the value of IC50 reaches mu M grade to show cytotoxicity similar to positive control polyenic taxusol; and significant microtubulin polymerization retardation activity and DNA intercalation function are presented in primary activity mechanism research; therefore, the compound is expected to be a new antineoplastic reagent with double functions of micromolecular microtubulin and DNA. The gamma-carboline derivative has the advantages of reasonable design, wide source of raw materials, easy preparation, mild reaction condition, simple operation and practicality. The structural formula of the compound is shown as the above.

Description

technical field [0001] The invention belongs to the synthesis of organic compounds, and relates to the synthesis of gamma-carboline derivatives and their application in the preparation of antitumor drugs. Background technique [0002] Anti-mitotic agents are a class of very effective anti-tumor drugs, which can stop the cell cycle of tumor cells in the mitotic phase (M phase), induce apoptosis, and cause tumor shrinkage or necrosis. Tubulin is an important target of anti-mitotic agents, and drugs can inhibit the polymerization or depolymerization of microtubules by binding to different sites on tubulin. Although the development of microtubule-targeting agents has been very successful, paclitaxel and vinblastine compounds that act on tubulin have been widely used in the clinical treatment of various tumors, however, these tubulin inhibitors often have the following problems: as structurally complex Natural products have limited sources and are difficult to synthesize; they c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61K48/00A61P35/00
Inventor 胡永洲陈静刘滔杨波何俏军吴睿楼剑书董晓武
Owner ZHEJIANG UNIV
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