Boric acid and borate compounds and application thereof

A compound and boric acid technology, applied in the direction of active ingredients of boron compounds, compounds containing elements of group 3/13 of the periodic table, drug combinations, etc., can solve problems such as no compound activity reports

Active Publication Date: 2017-11-28
CHENGDU ORIGIN BIOTECH LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The above-mentioned patent studies the compound as a prodrug of Ixazomib, which is metabolized into Ixazomib after oral ab

Method used

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  • Boric acid and borate compounds and application thereof
  • Boric acid and borate compounds and application thereof
  • Boric acid and borate compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0190] Example 1 Preparation of intermediate S3-1 of the present invention and target compound I-1-1

[0191] The synthetic route is as follows:

[0192]

[0193] CN200780100142 discloses a method for synthesizing a compound similar to the present invention; it uses TBTU and the like as a condensing agent to react the condensation intermediate S1 of substituted benzoic acid and glycine with amino borate S2, but the inventors found , The compound disclosed in the present invention is prepared using the above-mentioned patent disclosure route, and the product obtained is mainly the by-product S4-1 of deboronic ester. The specific operation is as follows:

[0194] The starting material (S-1-1) 0.205g (0.70mmol) in 10mL DMF solution, add 0.248g (0.74mmol) and 0.267gS2 (0.70mmol, 1eq) of condensing agent TBTU, reduce the temperature to about 0 degrees, drop DIEA 0.367 mL (2.1 mmol). After the reaction, the organic layer was added with 100 mL of water, extracted with dichloromethane, drie...

Example Embodiment

[0208] Example 2 Preparation of compound I-1-2 of the present invention

[0209]

[0210] The boric acid starting material (I-1-1) 5g (12.3mmol), dipropanolamine (S-3-2, molecular weight 133.19) 1.95g (14.6mmol), 20mL ethyl acetate, stirred overnight at room temperature, precipitation A white solid was filtered to obtain 4.8 g of compound I-1-2 with a yield of 78%, namely 2-chloro-5-bromo-N-[(R)-1-[1,3,7,2]-dioxazepine Hetero-2-boryl-3-methyl-butanocarboxamido]-methyl]-benzamide.

[0211] 1 H NMR(300MHz,DMSO-d6)δ(ppm)8.95(brs,1H),7.63-7.68(m,2H),7.48-7.50(m,1H), 6.63(d,1H,J=8.61Hz), 4.81 (m, 1H), 3.87-3.92 (m, 1H), 3.75 (m, 1H), 3.65 (m, 4H), 3.20-3.34 (m, 3H), 2.66 (m, 2H), 1.89-1.99 ( m,1H),1.63-1.66(m,1H),1.49(m,2H),1.29-1.34(m,1H),1.15-1.23(m,1H),0.94-0.98(m,1H),0.83( d, 6H).

[0212] ESI m / z: 500.0[M-H] - .

[0213] Compound I-1-2 was obtained according to the above preparation process, and it was detected at a temperature of 20~25℃. The X-ray powder diffraction pattern of th...

Example Embodiment

[0215] Example 3 Preparation of compound I-1-3 of the present invention

[0216]

[0217] Dissolve 2.25 g (5.55 mmol) of boric acid raw material (I-1-1) in 45 ml of ethyl acetate, stir at room temperature for 5 min, and add 0.61 g (5.82 mmol) of diethanolamine (S-3-3) dropwise. A white solid precipitated in the reaction liquid. After the dropwise addition was completed, stirring was continued for 2 hours, and 2.4 g of compound I-1-3 was obtained by suction filtration with a yield of 91%.

[0218] 1 H NMR(300MHz,DMSO-d6)δ(ppm)8.85(brs,1H),7.64-7.69(m,2H),7.48-7.52(m,1H), 7.00(d,1H,J=7.62Hz), 6.59(m,1H), 3.80-3.85(m,2H), 3.68(m,3H), 3.58(m,1H), 3.14(m,1H), 2.99(m,2H), 2.74-2.79(m, 2H), 1.59 (m, 1H), 1.29-1.32 (m, 1H), 1.19-1.13 (m, 2H), 0.82 (d, 6H).

[0219] ESI m / z: 475.9[M+H] + .

[0220] Compound I-1-3 was obtained according to the above preparation process, and it was detected at a temperature of 20~25℃. The X-ray powder diffraction pattern of this crystal form is shown in the a...

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Abstract

The invention discloses compounds shown in the formula (I) and further provides pharmaceutically acceptable salt, a preparation method and an application of the compounds and medicine composition of the compounds. The compounds have a remarkable inhibiting function on tumor cells, can be used for preventing and/or treating tumor related diseases, especially breast cancer, colon cancer, lung cancer, multiple myeloma and the like and have wide application prospects.

Description

technical field [0001] The invention belongs to the field of chemical medicine, 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 nu...

Claims

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Application Information

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IPC IPC(8): C07F5/02A61K31/69A61P35/00
CPCC07F5/025A61K31/69C07F5/02
Inventor 广兵阳泰董韧涵刘进覃传军谢建彭向阳钟月玲
Owner CHENGDU ORIGIN BIOTECH LTD
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