A substituted boronic acid compound, a pharmaceutical composition comprising the compound and its use

A compound and composition technology, applied in the field of medicine, can solve the problems of fast clearance rate, short half-life, low in vivo stability, etc.

Active Publication Date: 2019-06-14
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Marketed drugs and reported boronic acid proteasome inhibitors such as WO2005/021558, WO2005/016859, WO2006/086600, WO2009/02044, WO2010/012222, WO2011/109355, WO2011/026349, WO201

Method used

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  • A substituted boronic acid compound, a pharmaceutical composition comprising the compound and its use
  • A substituted boronic acid compound, a pharmaceutical composition comprising the compound and its use
  • A substituted boronic acid compound, a pharmaceutical composition comprising the compound and its use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 Preparation of (R)-(1-(2-(2,5-dichlorobenzamido)-2,2-d2-acetamido)-3-methylbutyl base) boronic acid (compound I-1)

[0045]

[0046] Concrete synthetic steps are as follows:

[0047]

[0048] Step 1: Synthesis of 2,2-d2-glycine (Compound 3).

[0049] Add glycine (200mg, 2.66mmol) and salicylaldehyde (0.04mL, 0.376mmol) into the reaction flask, add 10mL of deuterated acetic acid to dissolve, heat to 100°C under nitrogen protection, stir for 2 hours, cool to room temperature, concentrate to remove acetic acid Then add 2 mL of heavy water, stir at room temperature for 15 minutes, then add a small amount of water to dilute, add activated carbon for decolorization for 0.5 hours, filter, and concentrate the filtrate to dryness. Add a small amount of methanol, stir to precipitate a white solid, filter, and vacuum dry to obtain 176.7 mg of the product, yield: 88%. LC-MS(APCI):m / z=78.1(M+1) + .

[0050] Step 2: Synthesis of 2,5-[(dichlorobenzoyl)amino]-d2-...

Embodiment 2

[0064] Example 2 Preparation of (R)-(1-(2-(2,5-dichlorobenzamido)acetamido)-1-d-3-methylbutyl)boron Acid (Compound I-2)

[0065]

[0066] Concrete synthetic steps are as follows:

[0067]

[0068] Step 1: Synthesis of 2,5-[(dichlorobenzoyl)amino]acetic acid (compound 13).

[0069] Add glycine (1.125g, 15mmol) and sodium hydroxide (750mg, 18.75mmol) to the reaction flask, add 7.5mL water to dissolve, add dropwise 2,5-dichlorobenzoyl chloride (623.7mg, 3.0mmol) under ice bath 1mL tetrahydrofuran solution, the addition was completed, and the reaction was stirred for 1 hour. After the reaction was detected by TLC, the pH was adjusted to acidic with dilute hydrochloric acid, and a white solid was precipitated, filtered, washed with ice water, and vacuum-dried to obtain 675 mg of the product, with a yield of 91.1%. LC-MS(APCI):m / z=248.3(M+1) + .

[0070] Step 2: Synthesis of (S)-1-chloro-1-d-3-methylbutylboronic acid-(+)-pinanediol ester (compound 14).

[0071] Add co...

Embodiment 3

[0080] Example 3 Preparation of (R)-(1-(2-(2,5-dichlorobenzamido)acetamido)-2,2-d2-3-methylbutyl) Boronic acid (Compound I-3)

[0081]

[0082] Concrete synthetic steps are as follows:

[0083]

[0084] Step 1: Synthesis of 1,1-d2-2-methylpropanol (compound 19).

[0085] Ethyl isobutyrate (580.8 mg, 5 mmol) was dissolved in anhydrous THF (20 mL), and LiAlD was added in portions under ice-cooling 4 (230.9mg, 5.5mmol), after the addition, it was raised to room temperature and reacted overnight. After the reaction was detected by TLC, sodium sulfate decahydrate was added under ice bath to quench the reaction, filtered to remove insoluble matter, and the filtrate was concentrated to obtain 246mg of product, yield 64.73% . Jump straight into the next step.

[0086] Step 2: Synthesis of 1,1-d2-bromoisobutane (compound 20).

[0087] Compound 19 (850 mg, 11.17 mmol) and carbon tetrabromide (3.7 g, 11.17 mmol) were dissolved in dichloromethane (15 mL), and triphenylphosph...

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Abstract

It relates to a substituted boronic acid compound, a pharmaceutical composition containing the compound and its use. The substituted boronic acid compound is, for example, a compound represented by formula (I), or its crystal form, pharmaceutically acceptable salt, or prodrug , stereoisomers, hydrates or solvates. The boronic acid compound has proteasome inhibitory activity, has better pharmacodynamics/pharmacokinetic properties, has good applicability and high safety, and can be used for preparing medicines for treating diseases related to proteasomes. Formula 1)

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a substituted boronic acid compound and a pharmaceutical composition containing the compound, which can be used to prepare medicines for treating related diseases mediated by proteasomes. Background technique [0002] Proteasome is a huge multivalent complex enzyme, which is involved in many important physiological and biochemical processes in cells, such as DNA repair, cell cycle operation, signal transduction, antigen presentation, protein transmembrane localization, etc. Plays a major role in the balance of important intracellular enzymes. The function of proteasome is realized through ubiquitin-proteasome pathway (UPP). UPP not only catalyzes the degradation of abnormal proteins, but also participates in many regulatory and protein renewal and processing processes. The catalytic processes of these proteins are involved in important biochemical mechanisms of hum...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07K5/06C07H23/00A61K31/69A61P35/00A61P9/00A61P29/00A61P37/00A61P13/12
CPCA61P35/00C07F5/025C07B59/004C07B2200/05A61P35/02A61K9/0019A61K9/0053C07F5/02A61P29/00C07K5/06C07H23/00A61K31/69A61P9/00A61P13/12A61P37/00
Inventor 王义汉赵九洋
Owner SHENZHEN TARGETRX INC
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