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O-glycoprotein-2-acetamido-2-deoxy-3-d-glycopyranosidase inhibitors

A CR2R2, C3-C10 technology, applied in the field of O-glycoprotein-2-acetylamino-2-deoxy-3-D-pyranosidase inhibitors, can solve problems such as complex application

Pending Publication Date: 2021-01-12
BIOGEN MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, a major challenge in developing inhibitors for blocking the function of mammalian glycosidases, including O-GlcNAcase, is the large number of functionally related enzymes present in higher eukaryotic tissues
Therefore, the use of nonselective inhibitors to study the cellular and organismal physiological roles of a specific enzyme is complicated by the fact that complex phenotypes result from the concomitant inhibition of these functionally related enzymes

Method used

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  • O-glycoprotein-2-acetamido-2-deoxy-3-d-glycopyranosidase inhibitors
  • O-glycoprotein-2-acetamido-2-deoxy-3-d-glycopyranosidase inhibitors
  • O-glycoprotein-2-acetamido-2-deoxy-3-d-glycopyranosidase inhibitors

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Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0163]

[0164] N-(5-((3-(4-fluorobenzyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: to 3-(4-fluorobenzyl)piperidine (0.054g , 0.279 mmol) in MeOH (15.0 mL) were added N-(5-formylthiazol-2-yl)acetamide (0.095 g, 0.559 mmol) and a drop of AcOH. The mixture was stirred at 50 °C for 2 h. Add NaBH 3 CN (0.053 g, 0.838 mmol) and the mixture was stirred at 50 °C for 17 h. By preparative HPLC {(column: Waters Xbridge PrepOBD C18 150x30 5u; condition: water (0.04%NH 3 h 2 O+10mM NH 4 HCO 3 )-MeCN; Start at B: 35; End at B: 65; Gradient time (min): 10; 100% B hold time (min): 2; Flow rate (ml / min): 25} Purify the mixture to provide the title compound (0.038g, 39%). LCMS: [M+H] 348. 1 HNMR: (400MHz, methanol-d4) δ7.19(s, 1H), 7.14-7.10(m, 2H), 6.94(t, J=9.2Hz, 2H), 3.65(s, 2H), 2.83-2.75( m,2H),2.48(d,J=6.8Hz,2H),2.19(s,3H),2.02-1.99(m,1H),1.82-1.66(m,4H),1.57-1.47(m,1H) ,0.99-0.91(m,1H).

Embodiment 1-2

[0166]

[0167] N-(5-((3-(pyridin-2-ylmethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: to 2-(3-piperidinylmethyl)pyridine To a suspension of HCl (0.035 g, 0.165 mol, hydrochloride) and N-[5-(chloromethyl)thiazol-2-yl]acetamide (0.032 g, 0.165 mmol) in MeCN (0.64 mL) was added Triethylamine (0.05 g, 0.494 mol) and the mixture was warmed to 70 °C overnight. The reaction was cooled to room temperature, and the mixture was diluted with EtOAc and washed with saturated NH 4 Cl(aq) washes. via MgSO 4 The organics were dried, filtered and concentrated in vacuo. The residue was purified by preparative HPLC {(column: Waters XSelect CSH PrepC18 5um OBD 19x100mm; conditions: water: MeCN gradient 5-55% ACN, 7min gradient, 0.1 Vol% aluminum hydroxide modifier} to afford the title compound (0.015 g, 27%). LCMS (ESI): [M+H] 331. 1 HNMR: (500MHz, CDCl 3 )δ11.76(br s,1H),8.45(dd,J=1.8,4.9Hz,1H),8.40(d,J=1.8Hz,1H),7.47(td,J=1.8,7.9Hz,1H) ,7.21(dd,J=4.6,7.0Hz,1H),7.18(s,1H),3.70-3.5...

Embodiment 1-3

[0169]

[0170] N-(5-((3-(3-methoxybenzyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was obtained from 3- ((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylic acid tert-butyl ester, 1-bromo-3 - Preparation from methoxybenzene and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 360. 1 HNMR: (400MHz, methanol-d4) δ7.20(s, 1H), 7.13(t, J=8.0Hz, 1H), 6.71-6.69(m, 3H), 3.75(s, 3H), 3.71-3.65( m,2H),2.84-2.78(m,2H),2.48-2.46(m,2H),2.19(s,3H),2.04-1.99(m,1H),1.88-1.66(m,4H),1.58- 1.48(m,1H),1.00-0.92(m,1H).

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Abstract

Described herein are compounds represented by formula (I") or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same and methods of preparing and using the same. The variables Ar, Ra, Rb, m, n, Y1, Y2, R3 and R4 are defined herein.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 699,443, filed July 17, 2018; U.S. Provisional Application No. 62 / 690,536, filed June 27, 2018; and US Provisional Application No. 62 / 642,932; the entirety of each of said US Provisional Applications is incorporated herein by reference. Background technique [0003] A variety of cellular proteins in the nucleus and cytoplasm are post-translationally modified by the addition of the monosaccharide 2-acetylamino-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine) via O-glycoside key connection. This monosaccharide is commonly referred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzyme responsible for the post-translational attachment of β-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues of numerous nucleoplasmic proteins is O-GlcNAc transferase (OGTase). A second enzyme (called O-glycoprotein-2-acetylamino-2-deoxy-3-D-glucopyranosid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06C07D417/14C07D495/04A61P25/28A61K31/427A61K31/445
CPCC07D417/14C07D495/04A61P25/28C07D417/06C07D471/04
Inventor N.杰农K.M.古基恩J.维塞尔斯L.张R.吉亚纳塔西奥E.Y.S.林Z.辛
Owner BIOGEN MA INC