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3,4-dihydrobenzo[f][1,4]thiazepine compound or salts of same and medical use of same

A compound, the technology of dihydrobenzene, applied in the direction of drug combination, organic chemistry, anti-tumor drugs, etc., can solve the problem of inactivation

Inactive Publication Date: 2013-05-29
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Amino acid residues after GSK-3 autophosphorylation can occupy this special region and lead to the inactivation of GSK-3

Method used

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  • 3,4-dihydrobenzo[f][1,4]thiazepine compound or salts of same and medical use of same
  • 3,4-dihydrobenzo[f][1,4]thiazepine compound or salts of same and medical use of same
  • 3,4-dihydrobenzo[f][1,4]thiazepine compound or salts of same and medical use of same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 4-Benzyl-3,4-dihydro-2-phenylbenzo[f][1,4]thiazepine-5(2H)-hetero Preparation of ketone (HZkca) 1.1 Preparation of β-nitrostyrene (HZkc01)

[0037]

[0038] Dissolve 11.2g (200mmol) of KOH in 56mL of water, stir and cool in an ice-water bath; then add CH 3 NO 2 7.2g (120mmol), stirred for 5 minutes; dropwise added methanol solution (32mL) of 10.6g (100mmol) of benzaldehyde within 40 minutes; 30ml (600mmol) of concentrated hydrochloric acid was stirred for 10 minutes; the resulting solid was suction filtered and washed with water to obtain 12.2g (81.8mmol) of bright yellow needle crystals, with a yield of 81.8%.

[0039] 1 HNMR (400MHz, CDCl 3 ): δppm 8.02 (d, 1H, J=13.69Hz, -C H =C); 7.60(d, 1H, J=13.70Hz, =C H -NO 2 ); 7.57-7.44 (m, 5H, PhH).

[0040] 1.2 Preparation of 2-{[(α-(nitromethyl)benzyl]thiobenzoic acid (HZkc02)

[0041]

[0042] 12.2g (81.8mmol) of β-nitrostyrene, 12.67g (81.8mmol) of thiosalicylic acid, and 70mL of absolute ethanol were adde...

Embodiment 2

[0061] 4-(4-nitrobenzyl)-3,4-dihydro-2-phenylbenzo[f][1,4]thiazepine-5(2H)-hetero Preparation of ketone (HZkcc)

[0062]

[0063] The benzyl bromide in Step 1.6 of Example 1 is replaced by p-nitrobenzyl bromide, and the remaining raw material reagents and preparation methods are the same as in Example 1 to obtain the product 4-(4-nitrobenzyl)-3,4-dihydro -2-Phenylbenzo[f][1,4]thiazepine-5(2H)-hetero Ketone, yellow sand crystal, yield 51.2%.

[0064] 1 HNMR (400MHz, CDCl 3 ): δppm 8.22 (d, 1H, J = 8.71Hz, PhH); 8.07 (d, 1H, J = 8.41Hz, PhH); 7.83-7.81 (dd, 1H, J = 1.40Hz, 5.62Hz, PhH); 7.59-7.47(m, 5H, PhH); 7.30-7.10(m, 5H, PhH); 5.06(d, 1H, J=15.50Hz, PhC H 2 ); 4.85 (d, 1H, J=15.52Hz, PhC H 2 ); 4.37 (dd, 1H, J = 4.81Hz, 11.04Hz, C H -CH 2 ); 3.68-3.62 (m, 1H, CH-C H 2 ); 3.52-3.47 (m, 1H, CH-C H 2 ).MS(+ESI)m / z: 391.1[M+H] + , 413.2[M+Na] + .

Embodiment 3

[0066] 4-(3-nitrobenzyl)-3,4-dihydro-2-phenylbenzo[f][1,4]thiazepine-5(2H)-hetero Preparation of ketone (HZkcd)

[0067]

[0068] The benzyl bromide in Step 1.6 of Example 1 is replaced by m-nitrobenzyl bromide, and the remaining raw material reagents and preparation methods are the same as in Example 1 to obtain the product 4-(3-nitrobenzyl)-3,4-dihydro -2-Phenylbenzo[f][1,4]thiazepine-5(2H)-hetero Ketone, yellow needle crystal, yield 86.2%.

[0069] 1 HNMR (400MHz, CDCl 3 ): δppm: 8.21(s, 1H, PhH); 8.18(d, 1H, J=6.83Hz, PhH); 7.83(dd, 1H, J=1.95Hz, 5.85Hz, PhH); 7.81(d, 1H, J=7.80Hz, PhH); 7.59-7.47(m, 4H, PhH); 7.30-7.25(m, 3H, PhH); 7.13(d, 1H, J=2.44Hz, PhH); 7.12(d, 1H, J=1.47Hz, PhH); 4.40(d,1H, J=15.12Hz, PhC H 2 ); 4.91 (d, 1H, J=15.11Hz, PhC H 2 ); 4.39 (dd, 1H, J = 4.88Hz, 10.73Hz, C H CH 2 ); 3.69-3.49 (m, 2H, CH-C H 2 ).MS(+ESI)m / z: 390.7[M+H] + ;412.6[M+Na] + .

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Abstract

The invention relates to 3,4-dihydrobenzo[f][1,4]thiazepine compound of the general formula I or salts of the same and medicinal use of the same, belonging to the field of pharmaceutical chemistry. The 3,4-dihydrobenzo[f][1,4]thiazepine compound can inhibit glycogen synthase kinase-3beta (GSK-3beta) and be used as the non-ATP competitive micromolecular inhibitor of the GSK-3beta to prepare medicaments used for preventing or treating diseases related to the GSK-3beta. The invention further discloses the application of a medical combination formed by the compound and pharmaceutically acceptablesalts of the same to preparation of medicaments for preventing or treating the diseases related to the GSK-3beta, such as diabetes, Alzheimer's diseases and tumors.

Description

Technical field: [0001] The invention belongs to the field of medicinal chemistry. Involving 3,4-dihydrobenzo[f][1,4]thiazepine Compounds or their salts and their medicinal uses. The 3,4-dihydrobenzo[f][1,4]thiazepine The compound can inhibit glycogen synthase kinase-3β (GSK-3β), and can be used as a non-ATP competitive small molecule inhibitor of GSK-3β to prepare medicines for preventing or treating diseases related to GSK-3β. Background technique: [0002] According to the forecast of the International Diabetes Federation, due to poor eating habits and lack of exercise, there will be as many as 300 million people with diabetes worldwide in 2025. Most of them are type 2 diabetic patients. In China, diabetes has become the third leading cause of death after cardiovascular diseases and tumors. [0003] Currently, the development of small molecule inhibitors of glycogen synthase kinase-3 (Glycogen Synthase Kinase-3, GSK-3) for the treatment of complex diseases, such as...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D281/10C07D417/10A61K31/554A61P3/10A61P25/28A61P35/00
Inventor 楚勇黄朝辉叶德泳胡海荣
Owner FUDAN UNIV
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