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New compounds II

A compound and solvate technology, applied in the field of new compound Ⅱ, can solve problems such as lithium poisoning and narrow therapeutic window

Inactive Publication Date: 2008-12-10
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of lithium are the narrow therapeutic window and the risk of lithium toxicity if the dose is too high

Method used

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  • New compounds II
  • New compounds II
  • New compounds II

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0301] N-(3-methoxypropyl)-2-[2-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-carboxamide hydrochloride

[0302]

[0303] The title compound was followed in general procedure B using 7-chloro-2-[2-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine (45 mg, 0.15 mmol from Example 1 ( a)) and 3-methoxypropylamine (55 mg, 0.62 mmol) afforded 19 mg (30%) of the title compound.

[0304] 1 H NMR (CD 3 OD) δppm 8.82(d, J=5.8Hz, 1H), 8.09-8.00(m, 2H), 7.98-7.87(m, 3H), 3.63-3.56(m, 2H), 3.53(t, J=6.1Hz , 2H), 3.35(s, 3H), 1.98-1.92(m, 2H); 19 F NMR (376MHz, CD 3 OD) δppm - 60.21 (s, 3F); MS (ESI) m / z 379 (M+1).

[0305] Example 1 (a) 7-chloro-2-[2-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine

[0306]

[0307] The title compound was prepared according to general method A using 2,3-diaminopyridine (0.272 g, 2.5 mmol) and 2-(trifluoromethyl)benzoic acid (0.475 g, 2.5 mmol). After purification by preparative HPLC, 0.545 g (73% yield) of the title compound was obta...

Embodiment 2

[0310] N-(3-methoxypropyl)-2-[3-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-carboxamide hydrochloride

[0311]

[0312] The title compound was followed in general procedure B using 7-chloro-2-[3-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine (80 mg, 0.27 mmol, from Example 2 ( a)) and 3-methoxypropylamine (65 mg, 0.73 mmol) afforded 8 mg (7%) of the title compound.

[0313] 1 H NMR (CD 3 OD) δppm 8.68(s, 1H), 8.66(d, J=5.6Hz, 1H), 8.59(d, J=7.8Hz, 1H), 7.99(d, J=7.8Hz, 1H), 7.93(d, J=5.6Hz, 1H), 7.87(t, J=7.8Hz, 1H), 3.65(t, J=6.8Hz, 2H), 3.58(t, J=6.1Hz, 2H), 3.37(s, 3H) , 2.02-1.96(m, 2H); 19 F NMR (376MHz, CD 3 OD) δppm - 64.82 (s, 3F); MS (ESI) m / z 379 (M+1).

[0314] Example 2 (a) 7-chloro-2-[3-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine

[0315]

[0316] The title compound was prepared according to general method A using 2,3-diaminopyridine (0.272 g, 2.5 mmol) and 3-(trifluoromethyl)benzoic acid (0.475 g, 2.5 mmol) to give 0.545 g (yield:...

Embodiment 3

[0319] N-(3-methoxypropyl)-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-carboxamide hydrochloride

[0320]

[0321] The title compound was followed in general procedure B using 7-chloro-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine (80 mg, 0.27 mmol, from Example 3 ( a)) and 3-methoxypropylamine (61 mg, 0.68 mmol) afforded 14 mg (20%) of the title compound.

[0322] 1 H NMR (CD 3 OD) δppm 8.70(d, J=5.8Hz, 1H), 8.51(d, J=8.3Hz, 2H), 7.97(d, J=8.3Hz, 2H), 7.95(d, J=8.3Hz, 1H) , 3.64(t, J=6.9Hz, 2H), 3.57(t, J=6.1Hz, 2H), 3.37(s, 3H), 2.12-1.82(m, 2H); 19 F NMR (376MHz, CD 3 OD) δppm - 65.09 (s, 3F); MS (ESI) m / z 379 (M+1).

[0323] Example 3 (a) 7-chloro-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine

[0324]

[0325] The title compound was prepared according to general method A using 2,3-diaminopyridine (0.272 g, 2.5 mmol) and 4-(trifluoromethyl)benzoic acid (0.475 g, 2.5 mmol) to give 0.514 g (yield: 69%) of the crude product.

[0...

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Abstract

The present invention relates to new compounds of formula (I) as a free base or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

Description

technical field [0001] The present invention relates to novel compounds of formula I in free base form or pharmaceutically acceptable salts, solvates or solvates of salts, pharmaceutical preparations containing said compounds and the use of said compounds in therapy. The invention further relates to processes for the preparation of compounds of formula I and novel intermediates used therein. Background technique [0002] Glycogen synthase kinase 3 (GSK3) is a serine / threonine protein kinase composed of two isoforms (α and β) encoded by different genes but with high homology. GSK3 is highly expressed in the central and peripheral nervous systems. GSK3 phosphorylates several substrates including tau, β-catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates and inactivates GSK3 on the serine 9 residue. [0003] Alzheimer's Disease (AD), dementia and taupathy ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P19/08A61P25/00A61P25/28A61P3/10
CPCC07D471/04A61P15/16A61P17/14A61P19/00A61P19/08A61P25/00A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P43/00A61P3/10A61K31/437
Inventor 珀·阿维森一世欧万·阿泽尔杰里米·伯罗斯海伦娜·吉贝克托拜厄斯·赖因迪迪尔·罗蒂希彼得·索德曼
Owner ASTRAZENECA AB