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Benzothiazinone compounds, and preparation method and medicinal application thereof

A benzothiazinone and compound technology, applied in the field of medicinal chemistry, can solve the problems of small effect of ovarian cancer, selectivity and specificity that cannot be ignored, etc.

Active Publication Date: 2018-07-13
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2006, LiCl was reported to have a better anti-proliferation effect on ovarian cancer cells in vivo, but LiCl at physiological levels had little effect on ovarian cancer (Cao Q, et al., Cell Res. 16(2006) 671-677, Novetsky AP, et al., Int J Gynecol Cancer 23 (2013) 361-366)
[0006] Most of the GSK-3β inhibitors currently reported are ATP competitive inhibitors. Since the ATP binding region is highly conserved among more than 500 kinases, the selectivity and specificity problems caused by acting on this active region cannot be ignored.

Method used

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  • Benzothiazinone compounds, and preparation method and medicinal application thereof
  • Benzothiazinone compounds, and preparation method and medicinal application thereof
  • Benzothiazinone compounds, and preparation method and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of 4-ethyl-N-(1-nonanoylpiperidin-4-yl)-3-oxo-3,4-dihydro-(2H)benzo[1,4]thiazine-2-carboxamide ( 17a)

[0031] Preparation of 4-ethyl-(2H)1,4-benzothiazin-3(4H)-one (3)

[0032]

[0033] Into a 100 mL round bottom flask was added (2H)1,4-benzothiazin-3(4H)-one (2.5 g, 0.015 mol), sodium hydroxide powder (0.7 g, 0.016 mol), N,N-di Methylformamide (50mL) and ethyl bromide (1.5mL, 0.019mol) were reacted at room temperature, and the reaction was terminated by the disappearance of the raw material point as detected by TLC. Extracted with dichloromethane, combined organic layers, washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove solvent, and obtained 3.3 g of light yellow oil, which was directly used in Next reaction. Preparation of 2-methoxyformyl-4-ethyl-(2H)1,4-benzothiazin-3(4H)-one (5)

[0...

Embodiment 2

[0049] Preparation of N-(1-decanoylpiperidin-4-yl)-4-ethyl-3-oxo-3,4-dihydro-(2H)benzo[1,4]thiazine-2-carboxamide ( 17b)

[0050]

[0051] The preparation method was the same as that of 17a, except capric acid was used instead of nonanoic acid, the reaction solvent was N,N-dimethylformamide (DMF), the reaction temperature was 25°C, the catalyst was TBTU / DIPEA, and a white flaky solid was obtained with a yield of 46%. 1 H NMR (400MHz, DMSO-d6) δ8.12 (d, J = 7.6Hz, 1H), 7.39 (d, J = 7.6Hz, 1H), 7.30-7.29 (m, 2H), 7.05-7.04 (m, 1H),4.25(s,1H),4.16-3.90(m,3H),3.76-3.65(m,2H),3.10-3.00(m,1H),2.75-2.67(m,1H),2.26-2.25( m, 2H), 1.76-1.24 (m, 18H), 1.14 (t, J=6.8Hz, 3H), 0.85 (t, J=6.6Hz, 3H).

Embodiment 3

[0053] Preparation of 4-ethyl-3-oxo-N-(1-undecanoylpiperidin-4-yl)-3,4-dihydro-(2H)benzo[1,4]thiazine-2-carboxamide (17c)

[0054]

[0055] The preparation method is the same as 17a, using undecanoic acid instead of pelargonic acid, white flaky solid, yield 63%. 1 H NMR (400MHz, DMSO-d6) δ8.12 (d, J = 7.2Hz, 1H), 7.39 (d, J = 7.2Hz, 1H), 7.30-7.29 (m, 2H), 7.06-7.04 (m, 1H),4.25(s,1H),4.16-3.90(m,3H),3.76-3.65(m,2H),3.09-3.00(m,1H),2.75-2.67(m,1H),2.26-2.25( m, 2H), 1.76-1.24 (m, 20H), 1.14 (t, J = 7.0Hz, 3H), 0.85 (t, J = 6.4Hz, 3H).

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Abstract

The invention relates to benzothiazinone compounds with a general structural formula as shown in a formula I which is described in the specification, and a preparation method and medicinal applicationthereof, belonging to the field of pharmaceutical chemistry. The benzothiazinone compounds with the general structural formula as shown in the formula I are non-ATP competitive small-molecule inhibitors for glycogen synthase kinase-3beta (GSK-3beta), can selectively inhibit the activity of GSK-3beta and are applicable to preparation of drugs used for preventing or treating diseases related to GSK-3beta. The compounds as shown in the formula I have good in-vivo and in-vitro inhibition activity to tumors and can be used for preparing drugs for preventing or treating tumors. The invention also discloses a synthetic method for the benzothiazinone compounds with the general structural formula as shown in the formula I.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a novel benzothiazinone compound with the structure of formula I, a preparation method and a medicinal application thereof. The benzothiazinone compound of the formula I structure described in the present invention is an allosteric regulation inhibitor of glycogen synthesis kinase-3β (GSK-3β), which can inhibit the activity of GSK-3β at micromolar concentration, and is effective for various tested There was no significant inhibitory effect on protein kinases. The compound can be used for preparing medicine for treating ovarian cancer tumor or preparing medicine for preventing or treating diseases related to GSK-3β. Background technique [0002] The prior art discloses that glycogen synthase kinase-3β (Glycogen synthase kinase-3β, GSK-3β) is a highly conserved multifunctional serine / threonine protein kinase, because it can phosphorylate glycogen synthase and make It got its name...

Claims

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Application Information

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IPC IPC(8): C07D279/16C07D417/12A61K31/5415A61P35/00A61P3/10A61P25/28
CPCC07D279/16C07D417/12
Inventor 楚勇高扬叶德泳
Owner FUDAN UNIV
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