Deuterated dipeptide boric acids or esters thereof, and synthetic methods and uses of the compounds

A technology of dipeptide boronic acid and boric acid esters, which is applied in the field of deuterated dipeptide boronic acid or its ester compounds and their synthesis, and can solve neuropathy and other problems

Active Publication Date: 2017-07-04
NANJING LINGRUI PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current clinical data show that these drugs also have more side effects, such as fatigue, nausea, diarrhea, and neuropathy.

Method used

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  • Deuterated dipeptide boric acids or esters thereof, and synthetic methods and uses of the compounds
  • Deuterated dipeptide boric acids or esters thereof, and synthetic methods and uses of the compounds
  • Deuterated dipeptide boric acids or esters thereof, and synthetic methods and uses of the compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0155] Example 1: (S)-N-(2,5-dichlorobenzoyl)-2,2-dideuterateacetamide-D-leucine boronic acid citrate (compound NNU-459). synthetic route:

[0156]

[0157] Preparation of (S)-N-(2,5-dichlorobenzoyl)glycine (Ⅳ):

[0158] 2,5-Dichlorobenzoic acid (7.6 g, 40 mmol) and HOBt (8.1 g, 40 mmol) were dissolved in CH 2 Cl 2 (200mL), react at -10°C for 10min, add EDC.HCl (11.5g, 60mmol) and react for 30min, add compound II (5g, 40mmol), add DIPEA (18.1g, 140mmol) after reacting for 10min, and react for 20min Rise to room temperature to react overnight. TLC detects reaction, respectively with 10% hydrochloric acid solution (200mL), 5% NaHCO 3 the solution

[0159]

[0160] (200mL) and saturated brine (2×200mL) washing, CH 2 Cl 2 Anhydrous Na 2 SO 4 After drying, filtering, and evaporating the solvent under reduced pressure, 9.32 g of an oily compound was obtained, with a yield of 88.9%.

[0161] Compound III (129 mg, 0.31 mmol) obtained in the previous step was dissolved ...

Embodiment 2

[0171] Example 2: ((R)-1-(2-(2,5-benzamido)-2,2-didedeuteroacetamido)-3-methylbutyl)boronic acid diethanolamine ester (compound NNU- 458)

[0172]

[0173] According to the method described in Example 1, the difference is that diethanolamine was used instead of citric acid to prepare the target compound. 1 H NMR (400MHz, DMSO) 0.85-0.74 (-CH 3 ,m,6H),1.33-1.16(-CH 2 ,m,2H),1.64-1.51(-CH,m,1H),2.98-2.63(-CH 2 ,m,4H),3.13(-CH,td,J 1 =14.0Hz,J 2 =7.1Hz,1H),3.67(-CH 2 ,dd,J 1 =11.4Hz,J 2 =5.8Hz,4H),5.24(-NH,t,J=22.6Hz,1H),6.58(-NH,d,J=28.1Hz,1H),7.01(-NH,d,J=8.4Hz,1H ),7.65-7.43(-Ph,m,3H),8.79(d,J=36.3Hz,1H).MS(ESI):observed:m / z 432.3[M+H] +

Embodiment 3

[0174] Embodiment 3: pharmacokinetic evaluation in rats

[0175] Twelve SD male rats, weighing 220±20g, were randomly divided into four groups.

[0176] The two groups according to 0.500mg·kg -1 Dose: 0.100mg·mL by tail vein injection -1 For NNU-459 and MLN-9708, about 0.200 mL of blood was collected from the jugular vein at 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h and 36 h before administration and after administration, and placed in a -K 2 In a test tube, the plasma was separated after high-speed centrifugation (7800×g) for 5 minutes, and stored at -15°C to -35°C. It is used to compare the pharmacokinetic difference between NNU-459 and MLN-9708 administered by intravenous injection.

[0177] The other two groups received 1.50mg·kg -1 The dose of 0.150mg·mL was given by intragastric administration -1 For NNU-459 and MLN-9708, about 0.200 mL of blood was collected from the jugular vein at 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h and 36 ...

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PUM

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Abstract

Deuterated dipeptide boric acids or esters thereof, or crystal forms thereof, or pharmaceutically acceptable hydrates or solvates thereof are disclosed. The general structure of the compounds is shown as a formula (a) in the specification, wherein R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, deuterium or halogens, or C1-C4 alkyl one or a plurality of or all hydrogen atoms of which are deuterated; and at least one of the R1, the R2, the R3, the R4, the R5 and the R6 is deuterated or deuterium. The compounds can effectively inhibit proteasomes and effectively treat or prevent cancer, cardiovascular disease, inflammation, immune disease, nephropathy, vasculogenesis or prostate disease.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a deuterated dipeptide boronic acid or its ester compound and its synthesis method and application. Background technique [0002] The Ubiquitin-Proteasome Pathway (UPP) is the main pathway for the degradation of intracellular protein systems and is involved in many physiologically important cellular processes, including signal transduction, immune response, unfolded protein response and cell cycle progress. This pathway has an important relationship with the pathogenesis of cardiovascular and cerebrovascular diseases, cancer and neurodegenerative diseases. For this new target, the first proteasome inhibitor bortezomib (PS-341) was approved by the FDA in 2003 for the treatment of relapsed myeloma. In 2004, the drug was approved for marketing in the European Union for multiple myeloma. In September 2005, the drug was introduced by Xi'an Janssen and listed in Guangzhou, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07H23/00A61K31/69A61P35/00A61P9/00A61P29/00A61P37/00A61P13/12A61P13/08C07B59/00
CPCC07B59/001C07B59/002C07B59/005C07B2200/05C07F5/025C07H23/00
Inventor 朱永强雷萌白恩赫冯华云
Owner NANJING LINGRUI PHARM TECH CO LTD
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