Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Glycosidase inhibitors

A compound and general formula technology, applied in the direction of medical preparations containing active ingredients, biochemical equipment and methods, instruments, etc., can solve problems such as complex phenotypes

Active Publication Date: 2015-12-09
MERCK PATENT GMBH
View PDF15 Cites 11 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, a major challenge in developing inhibitors for blocking the function of mammalian glycosidases, including O-GlcNAcase, is the presence of large numbers of functionally related enzymes in higher eukaryotic tissues
Therefore, the use of non-selective inhibitors in the study of the cellular and in vivo physiological roles of a specific enzyme is difficult to achieve due to the complex phenotypes produced while inhibiting this functionally related enzyme

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Glycosidase inhibitors
  • Glycosidase inhibitors
  • Glycosidase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0316] Example 1: Preparation of 5-((4-phenylpiperidin-1-yl)methyl)thiazol-2-amine (intermediate)

[0317]

[0318] Step 1: To a solution of ethyl 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate (5 g, 0.0183 mol) in dry THF (80 mL) was added LiAlH dropwise with stirring at 0 °C under nitrogen atmosphere 4 (15 mL, 0.0309 mol, 2.0 M solution in THF). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was cooled to between -10°C and 0°C. The reaction was quenched by dropwise addition of 10% NaOH (5 mL). After 10 minutes, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give crude tert-butyl (5-(hydroxymethyl)thiazol-2-yl)carbamate (6 g) as a pale yellow solid. The crude product was used in the next reaction without purification. LC / MS: (Method A) 231.0 (M+H).

[0319] 1 HNMR (DMSO-d 6 , 400MHz): δ6.78(s, 1H), 4.38(s, 2H), 1.38(s, 9H).

[0320] St...

Embodiment 1-3

[0325] Example 1-3: Preparation of N-(5-((4-phenylpiperidin-1-yl)methyl)thiazol-2-yl)propionamide

[0326] To a stirred solution of 5-((4-phenylpiperidin-1-yl)methyl)thiazol-2-amine hydrochloride (100 mg, 1 eq.) in dichloromethane (5 mL) was added propionyl chloride ( 29mg, 1eq.) and triethylamine (96mg, 3eq.). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, water was added, and the product was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford N-(5-((4-phenylpiperidin-1-yl)methyl)thiazol-2-yl)propanamide trifluoroacetate as an off-white solid. Yield: 35% (41 mg). LC / MS: (Method A) 330.2 (M+H). HPLC: (Method A) Retention time: 3.03 min, 98.9%, (Max), 96.9% (254nm).

[0327] 1 HNMR (400MHz, DMSO-d 6 ): δ11.9(s, 1H)...

Embodiment 1-7

[0328] Example 1-7: Preparation of 2-methyl-5-((4-phenylpiperidin-1-yl)methyl)thiazole

[0329] Step 1: To a solution of ethyl 2-methylthiazole-5-carboxylate (1 eq) in dry THF (5 mL) was added LiAlH dropwise with stirring at 0 °C under nitrogen atmosphere 4 (1.1 eq., 2.0 M solution in THF). The reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to between -10°C and 0°C. The reaction was quenched by dropwise addition of 10% NaOH (5 mL). After stirring for 10 minutes, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give (2-methylthiazol-5-yl)methanol (6 g) as a pale yellow solid. The crude product was used in the next reaction without purification. LC / MS: (Method A) 130.0 (M+H).

[0330] 1 HNMR (DMSO-d 6 , 400MHz): δ7.4(s, 1H), 5.5(s, 1H), 4.6(d, J=4.0Hz, 2H), 2.6(s, 3H).

[0331] Step 2: To a s...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

Compounds of formula (I) wherein X1, X2, W, R1 to R5, L and m have the meaning according to the claims, are glucosidase inhibitors, and can be employed, inter alia, for the treatment of Alzheimer's disease.

Description

technical field [0001] The present invention relates to the medicine that comprises the compound represented by general formula (I) and / or its physiologically acceptable salt, [0002] [0003] In the formula, X 1 、X 2 , W, R 1 to R 5 , L and m have the meanings given in the claims. Compounds represented by general formula (I) are useful as glycosidase inhibitors. The object of the present invention also relates to the pharmaceutical composition comprising the compound represented by the general formula (I), and the application of the compound represented by the general formula (I) in the treatment of Alzheimer's disease. Background of the invention [0004] A large number of cellular proteins, including nuclear and cytoplasmic proteins, are post-translationally modified by the addition of the monosaccharide 2-acetylamino-2-deoxy-β-D-glucopyranoside (β-N-acetylglucoside), so These monosaccharides are attached to proteins via O-glycosidic bonds. This modification is...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D471/04C12Q1/34
CPCC07D417/06C07D277/46C07D413/06C07D417/14G01N33/6893A61K31/426A61K31/427A61K31/454A61K31/496A61K31/498A61P21/00A61P25/00A61P25/14A61P25/16A61P25/28A61P35/00A61P3/10
Inventor H·余L·刘-布加尔斯基T·L·约翰逊
Owner MERCK PATENT GMBH
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com