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Pyrano [3, 2 - d] [1, 3] thiazole as glycosidase inhibitors

A CH2, CY2 technology, applied in the field of Alzheimer's disease treatment, can solve complex phenotypes and other problems

Active Publication Date: 2014-07-16
MERCK PATENT GMBH
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  • 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

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  • Pyrano [3, 2 - d] [1, 3] thiazole as glycosidase inhibitors
  • Pyrano [3, 2 - d] [1, 3] thiazole as glycosidase inhibitors
  • Pyrano [3, 2 - d] [1, 3] thiazole as glycosidase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0245] Example 1: (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-[(4-pyridin-2-yl-1H-1,2,3-triazol-1-yl )methyl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (compound number 7)

[0246] Add (3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-(ethylamino)-5,6,7,7a- Tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (40.00mg; 0.15mmol; 1.00eq.), non-ACD supported copper (65.10mg; 1.02 mmol; 7.00eq.) and copper(2+) sulfate pentahydrate (7.31mg; 0.03mmol; 0.20eq.). The vial was evacuated and filled with nitrogen. This procedure was repeated twice, then ethanol (0.40ml) / water (0.60ml) / 2-methylpropan-2-ol (1.00ml) and 2-ethynylpyridine (0.03ml; 0.29mmol; 2.00eq .). The mixture was stirred overnight at room temperature, then 3 mL of water was added to the mixture, and dried by lyophilization. The mixture was purified on Yamazen C1 under acidic conditions to give 14.4 mg (20.1%) of the title compound as a white solid after lyophilization (HPLC 99%, retention time = 1.73 min).

[0247] 1 ...

Embodiment 2

[0249] Example 2: (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl ]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (Compound No. 2)

[0250] The title compound was prepared according to the above method using ethynylbenzene (0.01 ml; 0.11 mmol; 1.50 eq.). The mixture was purified on Yamazen Channel 2 (neutral conditions) to afford 8.4 mg (31%) of the title compound as a white solid after lyophilization.

[0251] 1 H NMR(DMSO-d6)δ8.30(S,1H), 7.75(d, J=7.2Hz, 2H), 7.48(dd, J=7.2,7.2Hz, 2H), 7.41(dd, J=7, 6, 7.6Hz, 1H), 6.21(d, J=6.0Hz, 1H), 4.63(dd, J=14.8, 8.0Hz, 1H), 4.17(dd, J=6.0, 6.0Hz, 1H), 4.05( dd, J=4.8, 4.8Hz, 1H), 3.92(dd, J=6.8, 6.8Hz, 1H), 3.54(dd, J=9.6, 4.8Hz, 1H), 3.20(m, 2H), 1.09(t , J=8.8Hz, 3H);

[0252] MS(m / z): 376[M+H] + .

Embodiment 3

[0253] Example 3: (3aR,5R,6S,7R,7aR)-5-[(4-benzyl-1H-1,2,3-triazol-1-yl)methyl]-2-(ethylamino )-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (Compound No. 14)

[0254] The title compound was prepared according to the above method using prop-2-yn-1-ylbenzene (0.03ml; 0.27mmol; 2.00eq.). The mixture was analyzed by Waters pre-HPLC (flow rate 40mL / min, the desired product was 2 O / ACN=64 / 36 effluent) purified to afford 26.3 mg (39%) of the title compound as a white solid after lyophilization.

[0255] 1 H NMR (D 2 O) δ7.82 (S, 1H), 7.25-7.40 (m, 5H), 6.47 (d, J=6.8Hz, 1H), 4.63 (dd, J=12.4, 4.4Hz, 1H), 4.20 (dd, J=6.8, 6.8Hz, 1H), 4.06(S, 2H), 4.01(m, 2H), 3.47(dd, J=9.6, 6.8Hz, 1H), 3.37(qd, J=7.2, 2.4Hz, 2H ), 1.21(t, J=6.8Hz, 3H);

[0256] MS(m / z): 390[M+H] + .

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Abstract

Novel compounds of formula (I), wherein R1 to R4 and X 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 compound represented by general formula (I) and / or its physiologically acceptable salt, [0002] [0003] In the formula, R 1 to R 4 and X 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 commonly referred to as O-linked N-acetylglucos...

Claims

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Application Information

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IPC IPC(8): C07D513/04A61K31/429
CPCC07D513/04C07H1/00C07H9/06C07H19/056A61P21/00A61P21/04A61P25/00A61P25/14A61P25/16A61P25/18A61P25/28A61P35/00A61P43/00A61P3/10A61K31/429A61K31/4439A61K31/454
Inventor M·唐纳利H·裘H·余L·刘-布加尔斯基A·古托普鲁斯
Owner MERCK PATENT GMBH
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