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2,3-dihydrobenzazapine*compound or its salt and its medical application
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A technology of heterochemicals and dihydrobenzene, which is applied in drug combination, organic chemistry, antineoplastic drugs, etc., and can solve problems such as multiple side effects
Active Publication Date: 2015-03-04
FUDAN UNIV
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Since the ATP binding region is highly conserved in other protein kinases, such inhibitors may cause more side effects, and improving the selectivity of their kinase action is the key to research and development
Method used
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Embodiment 1
[0037] Preparation of 5-(2-nitrobenzyl)-2,3-dihydro-2-phenyl[1,5]benzothiazepine -4-keto (LQaa)
[0038] (a). 2,3-dihydro-2-(2-phenyl)[1,5]benzothiazepine Preparation of -4(5H)-one (ZPa01)
[0039]
[0040] Cinnamic acid (28.4 g, 0.106 mol), o-aminothiophenol (13.3 g, 0.106 mol), and an appropriate amount of molecular sieves were reacted at 190° C. for 6.5 hours. Molecular sieves were removed by filtration, and the filtrate was cooled to precipitate a white solid, which was recrystallized from acetonitrile to obtain a white crystal with a yield of 25%. m.p.: 177.6-179.9°C. 1 H NMR (400MHz, CDCl 3 )δ: 8.30 (bd, 1H, N H ), 7.42-7.17 (m, 9H, PhH), 4.91-4.87 (m, 1H, C H -CH 2 ); 2.94-2.79 (m, 2H, CH-C H 2 ).MS (+ESI) m / z: 256.1 (M+H) + .
[0041] (b) Preparation of 5-(2-nitrobenzyl)-2,3-dihydro-2-phenyl[1,5]benzothiazepine -4(5H)-Kone (LQaa)
[0042]
[0043] Add compound ZPa01 0.255g (1mmol) and 60% NaH 0.0900g (3mmol) to 4ml reevaporated DMF, after stirring...
Embodiment 2
[0045] Preparation of 5-(3-nitrobenzyl)-2,3-dihydro-2-phenyl[1,5]benzothiazepine -4(5H)-Kone (LQac)
[0046]
[0047] The preparation method is the same as above LQaa, wherein 3-nitrobenzyl bromide is used instead of 2-nitrobenzyl bromide, 0.359 g of white solid, yield 92%. m.p.196.5-198.0. 1 H NMR (400MHz, CDCl 3 )δ: 8.17-8.07 (d, 2H, PhH), 7.74-7.13 (m, 11H, PhH), 5.58-5.54 (d, 1H, Ph-C H 2 ), 4.90-4.88 (m, 1H, Ph-C H 2 ), 4.87-4.84 (m, 1H, Ph-C H ), 2.96-2.83 (m, 2H, CH-C H 2 ).MS(+ESI)m / z: 390.9(M+H)+.
Embodiment 3
[0048] Example 3: Preparation of 5-(2-bromobenzyl)-2,3-dihydro-2-phenyl[1,5]benzothiazepine -4(5H)-Kone (LQad)
[0049]
[0050] The preparation method is the same as above LQaa, wherein 2-bromobenzyl bromide is used instead of 2-nitrobromobenzyl, 0.387 g of white solid, yield 91%. m.p.167.6-170.4. 1 H NMR (400MHz, CDCl 3 )δ: 7.62-7.07 (m, 13H, PhH), 5.25-5.23 (m, 2H, Ph-C H 2 ), 4.92-4.87 (m, 1H, Ph-C H ), 2.98-2.87 (m, 2H, CH-C H 2 ).MS(+ESI)m / z: 424.0(M+H)+, 426.4(M+H)+.
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Abstract
The invention belongs to the pharmaceutical chemistry field, and relates to a 2,3-dihydrobenzazapine*compound with a structure shown in a formula I, the 2,3-dihydrobenzazapine*compound is capable of inhibiting glycogen synthase kinase-3beta(GSK-3beta), and is a small-molecule inhibitor of GSK-3beta, a non ATP competition effect mode is taken for inhibiting the activity of GSK-3beta, no obvious inhibition effect is provided on the tested various proteinkinase, and the 2,3-dihydrobenzazapine*compound has high kinases selectivity, and can be used for preparing medicines for preventing or treating the diseases due to GSK-3beta abnormity. The invention further comprises an application of a pharmaceutically acceptable salt or a pharmaceutical composition of the compound for preventing or treating the relative diseases to GSK-3beta, the relative diseases to GSK-3beta are diabetes, Alzheimer's disease, stomachcancer, colorectal cancer, pancreascancer, liver cancer or mixed acute leukemia, but the relative diseases are not limited by the above diseases.
Description
Technical field: [0001] The invention belongs to the field of medicinal chemistry and relates to a class of 2,3-dihydrobenzazepines capable of inhibiting glycogen synthase kinase-3β (GSK-3β) This type of compound is a small molecule inhibitor of GSK-3β, which inhibits the activity of GSK-3β in a non-ATP competitive mode, and has no obvious inhibitory effect on various protein kinases tested, and has high kinase selectivity. It is used to prepare medicines for preventing or treating diseases caused by abnormalities of GSK-3β. Background technique: [0002] Glycogen Synthase Kinase-3β (Glycogen Synthase Kinase-3, GSK-3) is a multifunctional serine / threonineprotein kinase, which contains two subtypes of α and β in mammals, and its structure and function are very similar . Studies have shown that GSK-3 inhibitors can be applied to the treatment of complex diseases such as diabetes, early Alzheimer's disease, and cancer. In the insulinsignal transduction pathway, GSK-3β aff...
Claims
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