3-substituted-1,5-benzodiazepine compound and pharmaceutical application thereof

A technology of benzazepines and compounds, which is applied in the field of 3-substituted-1,5-benzazepinone compounds and their application in medicine, and can solve problems such as toxic and side effects

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

Studies have found that the level of GSK 3β that causes biological dysfunction in the body is only 2-3 tim

Method used

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  • 3-substituted-1,5-benzodiazepine compound and pharmaceutical application thereof
  • 3-substituted-1,5-benzodiazepine compound and pharmaceutical application thereof
  • 3-substituted-1,5-benzodiazepine compound and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation of (R)-N-(5-(2-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]sulfur nitrogen miscellaneous -3-base) benzamide (7), its structural formula is as follows:

[0037]

[0038] Step 1: Preparation of N-Boc-L-cysteine ​​(1)

[0039]

[0040] Add L-cysteine ​​(6.0g, 50mmol), NaOH (1.2g, 50mmol), dioxane (30mL) and water (50mL) into the reaction flask, add (Boc) 2 O (17.0 g, 70 mmol), continue stirring at room temperature overnight. Dioxane was removed by concentration under reduced pressure, and the aqueous layer was extracted with ethyl acetate to remove unreacted Boc anhydride. The aqueous layer was adjusted to pH 1-2 with 1 mol / L hydrochloric acid, extracted twice with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.15 g of a colorless syrup (1 ), yield 97%. directly used in the next step reaction;

[0041] The second ...

Embodiment 2

[0059] Example 2: Preparation of methyl-(R)-4-((5-(2-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydro-benzo[b][1, 4] Thiazepine -3-base) carbamoyl) benzoate (8), its structural formula is as follows:

[0060]

[0061] The preparation method was the same as that of compound 7 in Example 1, using monomethyl terephthalate instead of benzoic acid to obtain a white solid with a yield of 70%. 1 H NMR (400MHz, DMSO-d 6 )δ9.25-9.17(m,1H),8.07-8.00(m,3H),8.00-7.94(m,2H),7.79(d,J=8.2Hz,1H),7.68(d,J=7.8Hz ,2H),7.51(dd,J=13.7,8.0Hz,3H),7.33(d,J=9.1Hz,1H),5.45(d,J=17.3Hz,1H),5.31(d,J=17.3Hz , 1H), 4.67 (d, J = 9.7Hz, 1H), 3.86 (s, 3H), 3.62 (t, J = 9.3Hz, 1H).

Embodiment 3

[0062] Example 3: Preparation of (R)-4-methoxy-N-(5-(2-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydro-benzo[b][ 1,4] Thiazepine -3-base) benzamide (9), its structural formula is as follows:

[0063]

[0064] The preparation method was the same as the preparation of compound 7 in Example 1, replacing benzoic acid with p-methoxybenzoic acid to obtain a white solid with a yield of 50%. 1 H NMR (400MHz, DMSO-d 6 )δ8.78(d, J=7.6Hz, 1H), 7.98-7.91(m, 1H), 7.85-7.70(m, 3H), 7.60(d, J=8.1Hz, 2H), 7.47-7.35(m ,3H),7.22(dt,J=9.1,4.7Hz,1H),6.97-6.86(m,2H),5.39(d,J=17.3Hz,1H),5.23(d,J=17.2Hz,1H) , 4.68-4.55 (m, 1H), 3.71 (s, 3H), 3.58-3.47 (m, 1H), 3.30 (d, J=11.4Hz, 1H).

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PUM

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Abstract

The invention belongs to the technical field of medicine, and relates to a 3-substituted-1,5-benzodiazepine compound with a general molecular formula of a formula I and application of the 3-substituted-1,5-benzodiazepine compound to medicine. The 3-substituted-1,5-benzodiazepine compound can selectively inhibit the activity of glycogen synthase kinase-3beta (GSK 3beta) and can be used for the preparation of the medicine for preventing and/or treating diseases with abnormal pathological characteristics of the GSK 3beta, wherein the diseases includes cancer, neurological diseases, metabolic syndromes and the like. (Please see the specification for the formula.)

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a new class of 3-substituted-1,5-benzazepines with the structure of formula I Ketones and their applications in medicine. The 3-substituted benzazepine The compounds can selectively inhibit the activity of glycogen synthesis kinase-3β (GSK 3β), and can be used for the preparation of drugs for the prevention and / or treatment of diseases with abnormal pathological characteristics of GSK 3β, and the diseases include cancer, neurological diseases, metabolic syndrome etc. Background technique [0002] The prior art discloses that glycogen synthase kinase-3β (Glycogen synthase kinase-3β, GSK-3β) is a multifunctional serine / threonine protein kinase, which can phosphorylate and inactivate glycogen synthase. Studies have shown that GSK-3β can phosphorylate a variety of substrate proteins, participate in multiple important signal transduction pathways in vivo, including insulin signalin...

Claims

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Application Information

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IPC IPC(8): C07D281/10C07D417/12A61K31/554A61P35/00A61P35/02A61P25/00A61P29/00A61P3/00A61P3/10A61P25/28A61P25/16
CPCC07D281/10C07D417/12A61P35/00A61P35/02A61P25/00A61P29/00A61P3/00A61P3/10A61P25/28A61P25/16
Inventor 楚勇高扬叶德泳
Owner FUDAN UNIV
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