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3,4-dihydrogen-benzo[f][1,4] thiazepine*-5(2H)-ketones and their applications in medicine

A ketone compound, thiazepine technology, applied in the field of medicine, can solve the problems such as small effect of ovarian cancer, toxic and side effects, etc.

Active Publication Date: 2019-11-05
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)
Studies have found that the level of GSK-3β that causes biological dysfunction in the body is only 2-3 times the normal level, and excessive inhibition of its activity is likely to cause serious toxic side effects

Method used

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  • 3,4-dihydrogen-benzo[f][1,4] thiazepine*-5(2H)-ketones and their applications in medicine
  • 3,4-dihydrogen-benzo[f][1,4] thiazepine*-5(2H)-ketones and their applications in medicine
  • 3,4-dihydrogen-benzo[f][1,4] thiazepine*-5(2H)-ketones and their applications in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of 4-acryloyl-2-phenyl-3,4-dihydro-benzo[f][1,4]thiazepine -5(2H)-ketone (1), its structural formula is as follows:

[0028]

[0029] The first step: the preparation of (E)-2-nitrovinylbenzene

[0030]

[0031] Add benzaldehyde (10.6g, 0.1mol), nitromethane (10.7mL, 0.2mol), ammonium acetate (7.7g, 0.1mol), glacial acetic acid (100mL) into the reaction flask, and reflux for 3h. Add 200 mL of saturated brine, extract with ethyl acetate, combine the organic layers, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a dark brown solid, which was washed with methanol and filtered to obtain 6.8 g of a yellow needle-like solid with a yield of 46%, which was directly used in the next reaction.

[0032] The second step: the preparation of 2-((2-nitro-1-phenylethyl)thio)-benzoic acid

[0033]

[0034] Add (E)-(2-nitrovinyl)-benzene (6.7g, 0.04mol), mercaptosalicylic acid (6.9g, 0.04mol...

Embodiment 2

[0048] Example 2: Preparation of 4-acryloyl-2-(2-chlorophenyl)-3,4-dihydro-2-phenyl-benzo[f][1,4]thiazepine -5(2H)-ketone (2), its structural formula is as follows:

[0049]

[0050] White solid, yield 18%. ESI-MS m / z:344.1[M+H] + , 1 H NMR (400MHz, DMSO-d 6 )δppm7.84 (dd, J = 5.7, 3.4Hz, 1H), 7.71-7.61 (m, 2H), 7.58-7.47 (m, 2H), 7.39-7.24 (m, 2H), 7.24-7.09 (m, 2H), 6.39(dd, J=17.0, 2.1Hz, 1H), 5.95(dd, J=10.1, 2.0Hz, 1H), 5.03(dd, J=11.6, 5.1Hz, 1H), 4.61(dd, J = 15.0, 5.1 Hz, 1H), 3.58 (dd, J = 15.0, 11.5 Hz, 1H).

Embodiment 3

[0051] Example 3: Preparation of 4-acryloyl-2-(2-fluorophenyl)-3,4-dihydro-2-phenyl-benzo[f][1,4]thiazepine -5(2H)-ketone (3), its structural formula is as follows:

[0052]

[0053] A white solid was obtained with a yield of 55%. ESI-MS m / z:328.1[M+H] + , 1 H NMR (400MHz, DMSO-d 6 )δppm7.87-7.78(m,1H),7.64(t,J=4.4Hz,2H),7.61-7.55(m,1H),7.33(t,J=7.4Hz,1H),7.26-7.09(m ,4H),6.44-6.34(m,1H),5.94(dd,J=10.4,1.8Hz,1H),4.91(dd,J=11.6,5.1Hz,1H),4.61(dd,J=14.9,5.1 Hz, 1H), 3.56 (dd, J = 14.9, 11.7Hz, 1H).

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Abstract

The invention belongs to the technical field of medicine and relates to 3,4-dihydrogen-benzo[f][1,4] thiazepine*-5(2H)-ketones with the general structure of formula I and their applications in medicine. These compounds selectively inhibit the activity of glycogen synthesis kinases-3 beta (GSK 3beta), which can be used to prepare medicaments for preventing and / or treating diseases having GSK 3betaabnormal pathological characteristics, such as cancer, neurological diseases, inflammation, metabolic syndrome, and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a new class of 3,4-dihydro-benzo[f][1,4]thiazepines with the structure of formula I -5(2H)-ketone compounds and their medicinal uses. Formula I structure 3,4-dihydro-benzo[f][1,4]thiazepine described in the present invention -5(2H)-ketone compounds are non-ATP competitive inhibitors of glycogen synthesis kinase-3β (GSK-3β), which can inhibit the activity of GSK-3β at micromolar concentrations, and have no inhibitory effect on various protein kinases tested. No obvious inhibitory effect. The compound of the formula I has good in vitro inhibitory activity on cancers, such as ovarian cancer, and can be used to treat cancers such as ovarian cancer. The compound of formula I described in the present invention can be used to prepare medicines for preventing and / or treating diseases with abnormal pathological characteristics of GSK 3β, such diseases include cancer, neurological diseas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/10A61K31/554A61P35/00A61P35/02A61P25/28A61P25/16A61P25/00A61P21/00A61P3/10A61P29/00
CPCC07D281/10A61P35/00A61P35/02A61P25/28A61P25/16A61P25/00A61P21/00A61P3/10A61P29/00
Inventor 楚勇高扬叶德泳
Owner FUDAN UNIV
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