Novel boric acid derivative and medicinal composition

A boronic acid and compound technology, applied in the field of anti-tumor compounds and their pharmaceutical compositions, can solve problems such as unmet clinical needs of therapeutic drugs

Active Publication Date: 2018-08-24
CHENGDU ORIGIN BIOTECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Colon cancer is also a high-incidence tumor type. Although there are a large number of therapeutic drugs and methods, high-value therapeutic drugs in this field are still unmet clinical needs

Method used

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  • Novel boric acid derivative and medicinal composition
  • Novel boric acid derivative and medicinal composition
  • Novel boric acid derivative and medicinal composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Example 1 Preparation of compound I-1-1 of the present invention and its mannitol ester:

[0168]

[0169] (1) Dissolve 3 g (17.6 mmol) of the starting material (S-1-1) in 20 mL of dichloromethane solution, add 4.44 g (44.0 mmol) of NMM (N-methylmorpholine), and cool down to an internal temperature of 5 ℃, drop 2.29 g (21.1 mmol) of ethyl chloroformate, wait until the reaction is complete, and use the reaction solution for later use.

[0170] (2) Glycine 1.58g (21.1mmol) is dissolved in 30ml saturated sodium carbonate solution, is cooled to internal temperature 5 ℃, and step (1) gained reaction solution is added dropwise in this saturated sodium carbonate solution of glycine, internal temperature change control Within ±2°C, after the dropwise addition was completed, continue to stir at room temperature for 3h. Take the water layer, adjust the pH value to 2-3 with 15ml of dilute hydrochloric acid (2mol / ml), a solid precipitates, filter with suction, take the solid, a...

Embodiment 2

[0178] Example 2 Preparation of Compounds I-1-2, I-1-2-1, I-1-2-2, I-1-2-3, I-1-2-4 of the present invention

[0179]

[0180] Boric acid starting material (I-1-1) 5 grams (14.7mmol), diethanolamine (M2, molecular weight 105.14) 1.58 grams (15.0mmol), 20mL ethyl acetate, stirred overnight at room temperature, precipitated a white solid, filtered to obtain 4.8 gram compound I-1-2, yield 79%, namely 2-chloro-5-methyl-[(R)-1-[1,3,7,2]-dioxazepine-2-boryl- 3-Methyl-butyrocarboxamido]-methyl]-benzamide.

[0181] 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.69 (brs, 1H), 7.35-7.39 (m, 2H), 7.25-7.29 (m, 1H), 6.95 (d, 1H, J=4.71Hz ), 6.59(m, 1H), 3.74-3.79(m, 2H), 3.67(m, 3H), 3.57(m, 1H), 3.13(m, 1H), 2.99(m, 2H), 2.73-2.78( m, 2H), 2.31 (m, 3H), 1.59 (m, 1H), 1.18-1.30 (m, 2H), 0.81 (m, 6H).

[0182] ESI m / z: 410.32[M+H] + .

[0183] The mass spectrum of compound I-1-2 is as followsfigure 1 shown.

[0184] Similar to the synthesis of compound I-1-2, the boronic acid starting mat...

Embodiment 3

[0194] Example 3 Preparation of compounds I-1-3 and I-1-3-1 of the present invention

[0195]

[0196] Dissolve 2.25 g (6.61 mmol) of boric acid starting material (I-1-1) in 10 ml of ethyl acetate, add 0.92 g (6.94 mmol) of dipropanolamine (M3, molecular weight 133.19) under room temperature stirring, and continue stirring for 2 h. A precious solid was precipitated, and 2.05 g of compound I-1-3 was obtained by filtration, with a yield of 71%.

[0197] ESI m / z: 436.42[M-H] - .

[0198] Similar to the synthesis of compound I-1-3, I-1-3-1 was prepared by reacting boronic acid starting material (I-1-1) with M3-1 tripropanolamine.

[0199]

[0200] ESI m / z: 518.31[M+Na] + .

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Abstract

The invention discloses a novel boric acid derivative and a medicinal composition thereof, and belongs to the field of pharmaceutical chemistry. The boric acid derivative is a compound represented byformula (I). The invention also provides uses of the boric acid derivative in the preparation of an antitumor medicine or a proteasome inhibitor medicine. The uses concretely comprise a use of the boric acid derivative in the preparation of proteasome and chymotrypsin protease inhibitors, and a use in the preparation of medicines for preventing and / or treating multiple myeloma, colorectal carcinoma and other cancers. The novel boric acid derivative provides a new choice for clinically screening and / or preparing proteasome inhibitor medicines and multiple myeloma and colorectal carcinoma medicines, and has a wide application prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an antitumor compound and a pharmaceutical composition thereof. Background technique [0002] The ubiquitin-proteasome pathway-mediated protein degradation is an important mechanism for the body to regulate the level and function of intracellular proteins. Once the proteasome exceeds the normal level, it will lead to the weakening of growth inhibition, the reduction of apoptosis, and the promotion of angiogenesis, thereby triggering a variety of tumor diseases, so the proteasome is an important target for anticancer and other drugs. Proteasome inhibitors inhibit tumor cell growth and promote apoptosis by blocking cellular proteasome degradation. [0003] Multiple myeloma (multiple myeloma, MM) is a plasma cell carcinoma found in the bone marrow. In multiple myeloma, a group of plasma cells, or myeloma cells, transform into cancer cells and proliferate, making the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61K31/69A61P35/00
CPCA61P35/00C07F5/025A61K31/69C07F5/02C07F5/04
Inventor 广兵阳泰董韧涵刘进谢建秦岭钟月玲
Owner CHENGDU ORIGIN BIOTECH LTD
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