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Phenanthrene-indorisidine derivatives and nfκb inhibitors using them as active ingredients

A technology of active ingredients and substances, applied in the field of novel phenanthrene indolizidine alkaloid compounds or their salts, can solve the problems of strong cytotoxicity and difference, and achieve excellent solubility, less side effects, and excellent NFκB inhibitory effect. Effect

Inactive Publication Date: 2014-10-29
YAKULT HONSHA KK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, it is also known that sierphine exhibits strong cytotoxicity, and studies on the synthesis method are also being vigorously carried out (Non-Patent Document 13)
In addition, among the phenanthrene indolizidine alkaloids, it is known that isosilphine represented by the following formula (B) has central nervous system toxicity (Non-Patent Document 14)
In addition, in recent years, it has been known that sylphenine analogues represented by the following formulas (C) and (D) have shown strong cytotoxicity throughout the NCI60 cancer type panel test, and their mechanism of action is different from that of existing anticancer drugs. Tumor agents are different (Non-Patent Document 15)
In addition, it is known that a compound represented by the following formula (E), which is an insect-derived phenanthrene indolizidine alkaloid, has strong cytotoxicity (Non-Patent Document 16)

Method used

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  • Phenanthrene-indorisidine derivatives and nfκb inhibitors using them as active ingredients
  • Phenanthrene-indorisidine derivatives and nfκb inhibitors using them as active ingredients
  • Phenanthrene-indorisidine derivatives and nfκb inhibitors using them as active ingredients

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Experimental program
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Embodiment

[0194] Hereinafter, examples are shown and the present invention will be described in more detail, but the present invention is not limited thereto.

[0195] The phenanthrene indolizidine alkaloid of the present invention is synthesized according to the reaction pathway of the following steps 1-10. When the substituent represented by R needs to be protected, an appropriate protecting group is used for the reaction.

[0196]

Synthetic example 1

[0198] Synthetic R 1 ~R 6 Compounds represented by the following groups. The operation of steps 1 to 10 is as follows.

[0199] [Table 1]

[0200] Compound 1

[0201] R 1 R 2 R 3 R 4 R 5 R 6 H H H H OCH 3 OCH 3

[0202] Step 1: Synthesis of stilbene

[0203] In an eggplant-shaped flask, in 3,4-dimethoxyphenylacetonitrile 10.0g (56.43mmol) and benzaldehyde 5.99g (56.43mmol, 1.0eq.) in ethanol 150mL suspension, in an argon atmosphere, 380 mg (5.64 mmol, 0.1 eq.) of sodium ethoxide was added with stirring at room temperature, and heated to reflux (oil bath temperature: 85° C.). After 3 hours, the disappearance of the raw material was confirmed, and the reaction solution was cooled with an ice bath. The precipitated solid was suction-filtered with a Buchner funnel and a suction filter flask, and washed with 100 mL of methanol (twice). Drying was carried out at 60° C. under reduced pressure to obtain 13.70 g (92%) of...

Synthetic example 2

[0247] Synthetic R 1 ~R 6 Compounds represented by the following groups. The operations and the yield of each operation are shown below.

[0248] [Table 2]

[0249] Compound 29

[0250] R 1 R 2 R 3 R 4 R 5 R 6 Oh H H H OCH 3 OCH 3

[0251] Process 1

[0252] Yield: quant

[0253] 1 HNMR (400MHz, CDCl 3 )δ: 3.93 (3H, s), 3.96 (3H, s), 5.14 (2H, s), 6.92 (1H, dd, J=8.5Hz), 7.01-7.07 (1H, m), 7.14 (1H, d , J=2.4Hz), 7.26 (1H, dd, J=2.4, 8.5Hz), 7.31-7.48 (8H, m), 7.53-7.56 (1H, m)

[0254] Process 2

[0255] Yield: 88.7%

[0256] Separated as a mixture of positional isomers (isomer ratio 66:34) with respect to the benzyloxy group on the aromatic ring

[0257] Process 3

[0258] Yield: 97.6%

[0259] Separated as a mixture of positional isomers (isomer ratio 66:34) with respect to the benzyloxy group on the aromatic ring

[0260] Process 4

[0261] Yield: quant

[0262] Separated as a mixture of positional is...

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Abstract

A novel compound having an excellent NFºB inhibitory effect is provided. Specifically disclosed is a compound represented by the following formula (1) or a salt thereof: wherein, R 1 represents a hydrogen atom, a lower alkyl group, or the like; R 2 represents a hydrogen atom, a lower alkyl group, a halogen atom, or the like; R 3 represents a hydrogen atom, a lower alkyl group, a hydroxyl group, or a halogen atom; R 4 represents a hydrogen atom or a lower alkyloxy group; R 5 represents a hydrogen atom, a lower alkyloxy group, a halogen atom, a hydroxyl group, or a methylenedioxy group formed together with R 6 or an isopropylidenedioxy group formed together with R 6 ; R 6 represents a hydrogen atom, a lower alkyloxy group, or a methylenedioxy group formed together with R 5 or an isopropylidenedioxy group formed together with R 5 ; R 7 represents a hydrogen atom or a lower alkyl group; and R 8 represents a hydrogen atom, a hydroxyl group, an amino group, a lower alkylcarbonyloxy group, or a halogen atom.

Description

technical field [0001] The present invention relates to Nuclear Factor-κB (nuclear factor-κB, hereinafter, sometimes also referred to as NFκB) inhibitors. More specifically, it relates to a novel phenanthrene indorisidine alkaloid compound or a salt thereof that inhibits NFκB, and a drug containing them. Background technique [0002] NFKB exists as a dimer formed by various combinations of NFKB family members p50, p65 / RelA, c-Rel, Rel-B and p52. Among them, the most well-known dimer is a heterodimer formed by a 50 kDa subunit (p50) and a 65 kDa subunit (p65). [0003] The heterodimer usually exists in an inactive state combined with the inhibitor of NFκB (IκB) in the cytoplasm, but once the cells are stimulated by inflammatory cytokines or cell growth factors, etc., it will make IκB through the AKT signal transduction pathway, etc. Kinase activation, which causes the phosphorylation of IκB, the phosphorylated IκB is ubiquitinated and decomposed by the proteasome. As a resu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/444A61P1/00A61P3/04A61P3/10A61P9/08A61P9/10A61P11/06A61P17/00A61P17/06A61P19/02A61P25/28A61P29/00A61P31/04A61P31/12A61P35/00A61P35/04A61P37/02A61P37/06A61P37/08A61P43/00
CPCC07D471/04A61P1/00A61P11/06A61P17/00A61P17/06A61P19/02A61P25/28A61P29/00A61P3/04A61P31/04A61P31/12A61P35/00A61P35/04A61P37/02A61P37/06A61P37/08A61P43/00A61P9/08A61P9/10A61P3/10
Inventor 池田隆史泽田诚吾八重樫隆松崎健桥本秀介山崎龙太
Owner YAKULT HONSHA KK
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