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Benzomorpholone derivatives and their preparation and use

A technology of benzomorpholone and derivatives, which is applied in the field of benzomorpholone derivatives and their preparation, and can solve problems such as no drugs on the market and single structure type of small molecule inhibitors

Active Publication Date: 2021-02-05
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the structure type of the current small molecule inhibitors is still relatively single, and there is no drug on the market

Method used

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  • Benzomorpholone derivatives and their preparation and use
  • Benzomorpholone derivatives and their preparation and use
  • Benzomorpholone derivatives and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1 Preparation of N-(2-methyl-2H-1,4-benzomorpholine-3(4H)-one-7-yl)benzenesulfonamide (compound 1)

[0089]

[0090] (1) Synthesis of 2-methyl-7-nitro-2-hydrogen-1,4-benzomorpholin-3(4-hydrogen)-one:

[0091]

[0092] Add 125 mM potassium carbonate to 100 mL of dried DMF (N,N-dimethylformamide), add 50 mM 2-amino-5-nitrophenol to it and stir at room temperature for 1 h until it is completely dissolved. Under the condition of ice bath, a DMF solution of 50 mM ethyl 2-bromopropionate was slowly added dropwise. Half an hour later, the reaction solution was slowly raised to room temperature, and reacted at 90°C for 12h. After the reaction solution is cooled, part of the solvent is evaporated under reduced pressure. Slowly add 300-500mL of ice water under stirring conditions, and solids precipitate out. Stir under ice bath conditions for half an hour, filter, and vacuum-dry the filter cake to obtain a relatively pure intermediate product, which is brown. Powd...

Embodiment 2

[0102] Example 2 Preparation of 4-methyl-N-(2-methyl-2H-1,4-benzomorpholine-3(4H)-one-7-yl)benzenesulfonamide (compound 2)

[0103]

[0104] Using p-toluenesulfonyl chloride as raw material, it was prepared according to the preparation method of Example 1.

[0105] 1 HNMR (400MHz, DMSO-d6) δ10.55(s, 1H), 10.06(s, 1H), 7.60(d, J=8.2Hz, 2H), 7.35(d, J=8.1Hz, 2H), 6.75- 6.66(m,2H),6.65(s,1H),4.59(q,J=6.7Hz,1H),2.34(s,3H),1.36(d,J=6.8Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ166.36(s), 143.16(s), 142.95(s), 136.47(s), 132.82(s), 129.63(s), 126.67(s), 124.19(s) , 115.74(s), 114.66(s), 109.06(s), 72.62(s), 20.92(s), 15.95(s). ESI-MS:m / z:355.1[M+Na] + .

Embodiment 3

[0106] Example 3 Preparation of 4-chloro-N-(2-methyl-2H-1,4-benzomorpholin-3(4H)-one-7-yl)benzenesulfonamide (compound 3)

[0107]

[0108] Using p-chlorobenzenesulfonyl chloride as a raw material, it was prepared according to the preparation method of Example 1.

[0109] 1 HNMR(400MHz,DMSO-d6)δ10.52(s,1H),10.44(s,1H),7.99(d,J=7.4Hz,1H),7.63(d,2H),7.51(t,J=6.2 Hz,1H),6.69(d,J=11.2Hz,3H),4.62-4.54(m,1H),1.34(d,J=6.7Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ166.31(s), 143.00(s), 134.64(s), 131.94(s), 131.55(s), 115.77(s), 108.40(s), 72.62(s) ,15.95(s). ESI-MS:m / z:375.5[M+Na] + .

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Abstract

The invention belongs to the field of chemical medicines and particularly relates to a benzomorpholone derivative as well as a preparation method and application of the benzomorpholone derivative. The invention provides a benzomorpholone derivative with a structure as shown in the formula I and also provides a preparation method and application of the benzomorpholone derivative. The benzomorpholone derivative provided by the invention is novel in structure, has a good effect on selectively inhibiting BET targets, produces cytotoxicity for various tumor cells to different extents and is a novel BET small-molecule inhibitor. The compound disclosed by the invention has the potential to develop antitumor drugs.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and specifically relates to benzomorpholone derivatives and their preparation methods and applications. Background technique [0002] Bromodomain-containing proteins (BRDs) exist in many nuclear regulatory factors, and their sequences are variable, but they all carry a conserved fold structure, which consists of four left-handed α-helices (αZ, αA, αB and αC )constitute [1] , can specifically recognize ε-N-acetylated lysine residues, and play an important role in the recruitment of gene transcription factors to acetylated chromatin [2-3] . BRDs dysfunction is related to the occurrence of many diseases, especially closely related to the occurrence and development of tumors [4] . The human genome encodes more than 50 bromodomain proteins, which can be divided into 8 subfamilies from a phylogenetic perspective. BET (bromodomain and extra-terminal) is a special group of them. In mammals, the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/34C07D413/12A61P35/00
CPCC07D265/34C07D413/12
Inventor 余洛汀魏于全王宁宇刘利
Owner SICHUAN UNIV