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Acenaphtho-heterocycles compounds and application thereof in preparation of BH3 analogue Bcl-2 family protein inhibitor

A technology of heterocycles and compounds, applied in the field of simulating BH3-only proteins, can solve problems such as insufficient BH3 similarity, toxic side effects, and limited use range

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

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Problems solved by technology

But they all have shortcomings: Gossypol and Obatoclax have insufficient BH3 similarity, and are not absolute BH3 analogs, that is, they have cytotoxicity independent of BAX / BAK, indicating that there are other targets, so they have toxic side effects
Although ABT-737 is an absolute BH3 analogue, it cannot interact with Mcl-1 and cannot broadly inhibit Bcl-2 family proteins, thus severely limiting its scope of use

Method used

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  • Acenaphtho-heterocycles compounds and application thereof in preparation of BH3 analogue Bcl-2 family protein inhibitor
  • Acenaphtho-heterocycles compounds and application thereof in preparation of BH3 analogue Bcl-2 family protein inhibitor
  • Acenaphtho-heterocycles compounds and application thereof in preparation of BH3 analogue Bcl-2 family protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040]Add 1 gram of 8-oxo-8H acenaphtho[1,2-b]pyrrole-9-carbonitrile and 0.47 gram of p-cresol to 50 milliliters of acetonitrile, stir at reflux for 3 hours, evaporate part of the solvent, and separate the product by chromatography 3-(p-Tolyloxy)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile, yield 40%. M.p.232-233°C; 1H NMR (400M, CDCl3): δ8.916(dd, J=8.8Hz, 1H), 8.623(d, J=8.8Hz, 1H), 8.447(d, J=6.4Hz, 1H ), 7.859(t, J=8.0Hz, 1H), 8.324(d, J=8.4Hz, 2H), 7.101(d, J=8.4Hz, 2H), 7.016(d, J=8.4Hz, 2H), 3.256(s, 3H).

Embodiment 2

[0042] Weigh 0.93g of phenoxyacenaphthenequinone, dissolve 0.3g of malononitrile in dichloromethane, add to a silica gel column, rinse quickly, spin dry after passing through the column to obtain a red solid. 10.1 g was weighed, and the yield was 92%. Take 0.6g 3-phenoxy-(2-oxo-2hydro-acenaphthene)-malononitrile, add 0.08g K 2 CO 3 , 20ml of acetonitrile was heated to reflux for 3h, and the reaction solution was spin-dried after the reaction was completed. Chromatographic column separation (CH 2 Cl 2 : Petroleum ether=2:1) ​​an orange-red solid was obtained, and the isomer ratio of NMR was 1:0.3. Two isomers were separated using the preparative liquid phase.

[0043]

[0044] The first component A: M.p.265-267°C; 1 H NMR (400M, CDCl 3 ): δ 8.927(d, J=8.0Hz, 1H), 8.630(d, J=8.8Hz, 1H), 8.450(d, J=7.2Hz, 1H), 7.876(t, J=8.0Hz, 1H) , 7.754(t, J=8.0Hz, 2H), 7.392(t, J=7.6Hz, 1H), 7.233(d, J=7.6Hz, 2H), 7.028(d, J=8.4Hz, 1H).

[0045] The second component B: M.p.282-283...

Embodiment 3

[0047] Weigh 1.0 g of p-tolyloxyacenaphthenequinone, dissolve 0.3 g of malononitrile in dichloromethane, add to a silica gel column, rinse quickly, spin dry after passing through the column to obtain a red solid. Weighed 11.2 g, yield 93%. Take 0.7g 3-phenoxy-(2-oxo-2hydro-acenaphthene)-malononitrile, add 0.08g K 2 CO 3 , 20ml of acetonitrile was heated to reflux for 4h, and the reaction solution was spin-dried after the reaction was completed. Chromatographic column separation (CH 2 Cl 2 : Petroleum ether=1:1) to obtain an orange-red solid, and the ratio of isomers was 1:0.4 by NMR. Two isomers were separated using the preparative liquid phase.

[0048]

[0049] The first component A: M.p.232-233°C; 1 H NMR (400M, CDCl 3 ): δ 8.916(dd, J=8.8Hz, 1H), 8.623(d, J=8.8Hz, 1H), 8.447(d, J=6.4Hz, 1H), 7.859(t, J=8.0Hz, 1H) , 8.324(d, J=8.4Hz, 2H), 7.101(d, J=8.4Hz, 2H), 7.016(d, J=8.4Hz, 1H), 2.351(s, 3H).

[0050] The second component B: M.p.258-260°C; 1 H NMR (400M, C...

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Abstract

The invention relates to an acenaphthene merged heterocyclic ring compound and application to preparing BH3 analog Bcl-2 family protein inhibitor thereof. The compound introduces various oxo-substances and sulfo-substances, carbonyl compound and acyl compound in site of 3, 4 and 6 of 8-oxo-8H-acenaphthene merged [1, 2-b] pyrrole-9-nitrile, or further substitutes 9-nitrile as acid, ester acyl and amido. The acenaphthene merged heterocyclic ring compound simulates BH3-only protein to competitively combine and antagonize Bcl-2, Bcl-xL and Mcl-1 protein in vitro and in cells, so as to induce cell apoptosis. The compound can be used for preparing anticancer compounds.

Description

technical field [0001] The present invention relates to a new class of oxo, thio, ketone or ester substituted derivatives of 8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile and their in vivo and in vitro simulations The BH3-only protein competitively binds and antagonizes Bcl-2, Bcl-L and Mcl-1 proteins, thereby inducing cell apoptosis and being used as an anticancer compound. Background technique [0002] Molecularly targeted antineoplastic drugs are becoming a hot spot in new drug development and a new generation of market-oriented products after cytotoxic antineoplastic drugs. Bcl-2 protein is the most important molecular target for antagonizing and reversing the immortality of malignant tumors. Therefore, drugs that specifically antagonize Bcl-2 protein will finally achieve the goal of anti-cancer with high selectivity, safety, high efficiency and low pain by specifically inducing tumor cell apoptosis. Among Bcl-2 inhibitors, BH3 analogs (BH3mimetics) have the most si...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/70C07D405/12C07D409/12A61K31/403A61P43/00
CPCC07D209/70C08B37/0015A61K31/54C07D405/12C07D409/12A61K31/403A61P35/00A61P43/00C07D209/56C08B37/0012
Inventor 张志超吴桂叶宋婷
Owner DALIAN UNIV OF TECH
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