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New imidazo[ 4,5-b]pyridine-7-carboxamides 704

A technology of imidazo and pyridine, which is applied in the field of preparation compounds, can solve problems such as lithium poisoning and narrow therapeutic window

Inactive Publication Date: 2010-03-24
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 imidazo[ 4,5-b]pyridine-7-carboxamides 704
  • New imidazo[ 4,5-b]pyridine-7-carboxamides 704
  • New imidazo[ 4,5-b]pyridine-7-carboxamides 704

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0182] Methyl 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)benzoate

[0183]

[0184] Add DIPEA (16.6 mL, 95.7 mmol) to 5-bromopyridine-2,3-diamine (6.0 g, 31.9 mmol), monomethyl terephthalate (6.89 g, 38.3 mmol) and HBTU (14.5 g, 38.3 mmol) in MeCN (100 mL), then the reaction mixture was stirred at room temperature for 1 h. The precipitate formed was collected and washed with MeCN. The solid was partitioned into microwave vials using HOAc (4 mL) and heated to +200 °C for 5 min. The product precipitated at room temperature, was filtered, washed with HOAc and MeCN, and dried to afford 8.58 g (81% yield) of the title compound.

[0185] 1 H NMR (CDCl 3 )δppm; 8.15(d, J=1.52Hz, 1H), 8.07-8.09(m, 2H), 7.97(d, J=8.84Hz, 2H), 7.59(d, J=1.52Hz, 1H), 3.75( s, 3H); MS (APPI) m / z (M+1) 332, 334.

Embodiment 2

[0187] Methyl 4-(6-chloro-3H-imidazo[4,5-b]pyridin-2-yl)benzoate

[0188]

[0189] Add DIPEA (21.9 mL, 126 mmol) to 5-chloropyridine-2,3-diamine (6.0 g, 42.0 mmol), monomethyl terephthalate (9.06 g 50.3 mmol) and HBTU (19.1 g 50.3 mmol) suspension in MeCN (100 mL), the reaction mixture was then stirred at room temperature for 1 h. The precipitate formed was collected and washed with MeCN. The solid was partitioned into microwave vials using HOAc (4 mL) and heated to +200 °C for 10 min. The product precipitated at room temperature, was filtered, washed with HOAc and MeCN, and dried to afford 10.3 g (85% yield) of the title compound.

[0190] 1 H NMR (CDCl 3 )δppm; 7.92-7.98(m, 3H), 7.84(d, J=8.84Hz, 2H), 7.38(d, J=1.77Hz, 1H), 3.59-3.63(m, 3H); MS(APPI)m / z(M+1)288, 290.

Embodiment 3

[0192] Methyl 4-(6-bromo-7-chloro-3H-imidazo[4,5-b]pyridin-2-yl)benzoate

[0193]

[0194] Methyl 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)benzoate (6.7 g, 20.2 mmol) obtained in Example 1 and m-chloroperbenzoic acid (70 %, 17.75 g, 60.3 mmol) was stirred in HOAc at room temperature for 18 hours. Another 2 equivalents of m-chloroperbenzoic acid (70%, 9.06 g, 40.6 mmol) were added to the reaction mixture and stirring was continued for 6 hours. The solvent was evaporated in vacuo and the residue was crystallized from EtOH. The resulting solid was mixed with POCl 3 Mix and heat at +120°C for 5 minutes in a microwave reactor. After cooling to room temperature, the mixture was poured into an ice / water mixture and the formed precipitate was collected, washed with water and dried to afford 6.1 g (83% yield) of the title compound.

[0195] 1 H NMR (400MHz, DMSO-d 6 )δppm; 8.59(s, 1H), 8.40(d, J=8.53Hz, 2H), 8.15(d, J=8.53Hz, 2H), 3.91(s, 3H); MS(APPI) m / z(M +1)368.

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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 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 a process for the preparation of compounds of formula (I) and novel intermediates for use in this process. Background technique [0002] Glycogen synthase kinase-3 (GSK3) is a serine / threonine protein kinase composed of two isoforms (α and β), which are regulated by different genes encodes, but has high homology within the catalytic domain. 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. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/5375A61P19/08A61P25/00A61P25/28A61P3/10
CPCC07D471/04A61P17/14A61P19/08A61P19/10A61P25/00A61P25/14A61P25/16A61P25/22A61P25/24A61P25/28A61P3/10A61K31/437A61K31/5375
Inventor 珀·阿维森杰里米·伯罗斯彼得·索德曼乌尔里卡·英格夫
Owner ASTRAZENECA AB