New pyrimidine derivatives and their use in therapy as well as the use of pyrimidine derivatives in the manufacture of a medicament for prevention and/or treatment of alzheimer's disease

A technology of compounds and medicinal salts, which can be applied to medical preparations containing active ingredients, drug combinations, metabolic diseases, etc., and can solve problems such as lithium poisoning and narrow therapeutic windows

Inactive Publication Date: 2008-12-17
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 pyrimidine derivatives and their use in therapy as well as the use of pyrimidine derivatives in the manufacture of a medicament for prevention and/or treatment of alzheimer's disease
  • New pyrimidine derivatives and their use in therapy as well as the use of pyrimidine derivatives in the manufacture of a medicament for prevention and/or treatment of alzheimer's disease
  • New pyrimidine derivatives and their use in therapy as well as the use of pyrimidine derivatives in the manufacture of a medicament for prevention and/or treatment of alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0596] 4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[3-methoxy-5-(trifluoromethyl)phenyl]pyrimidin-2-amine

[0597] Embodiment 1 (a) 1,2-dimethyl-5-(trimethyltin base)-1H-imidazole

[0598]

[0599]1,2-Dimethylimidazole (0.960 g, 10.0 mmol) was diluted in anhydrous THF (50 mL) under argon, and the solution was cooled to -78°C. tert-Butyllithium (1.7M in pentane, 6.47 mL, 11.0 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred at -78 °C for 1 h, then treated with a solution of trimethyltin chloride (2.2 g, 11.0 mmol) in anhydrous THF (10 mL). The mixture was stirred at -78°C to room temperature for 60 hours. The solvent was then evaporated in vacuo to give the title compound (1.29 g, 50%). The crude product was used in the next step without further purification.

[0600] 1 H NMR (CDCl 3 )δppm 6.87 (s, 1H), 3.56 (s, 3H), 2.41 (s, 3H), 0.45-0.18 (m, 9H); MS (CI) m / z 261 ( 120 Sn)(M+1).

[0601] Embodiment 1 (b) 2-chloro-4-(1,2-dimethyl-1H-imidazo...

Embodiment 2

[0610] N-(3,5-dichlorophenyl)-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine

[0611]

[0612] The title compound was followed in general procedure C using 2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine (from Example 1(b)) (50 mg, 0.221 mmol ) and 3,5-dichloroaniline (39mg, 0.243mmol) to give the title compound (15mg, 19%).

[0613] 1 H NMR (DMSO-d 6 )δppm 10.12(s, 1H), 8.74(d, J=2.8Hz, 1H), 7.96(d, J=2.8Hz, 1H), 7.79(d, J=2.0Hz, 1H), 7.72-7.55(m , 1H), 7.16 (t, J = 1.8 Hz, 1H), 4.00 (s, 3H), 2.57 (s, 3H); MS (ESI) m / z 352 (M+1).

Embodiment 3

[0615] (4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}phenyl)(phenyl)methanone

[0616]

[0617] The title compound was followed in general procedure C using 2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine (from Example 1(b)) (80 mg, 0.354 mmol ) and (4-aminophenyl)(phenyl)methanone (84mg, 0.424mmol), Pd(OAc) 2 (4.7mg, 0.021mmol) and Pd(t-Bu 3 P) 2 (10.7 mg, 0.021 mmol) to give the title compound (56 mg, 41%).

[0618] 1 H NMR (CDCl 3 )δppm 8.32 (s, 1H), 8.00-7.63 (m, 7H), 7.60-7.33 (m, 4H), 3.96 (s, 3H), 2.51 (s, 3H); MS (ESI) m / z 388 ( M+1).

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PUM

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Abstract

The present invention relates to use of 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, as pharmaceutical ingredients for treatment of dementia, Alzheimer's Disease, Parkinson's Disease, Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Guam, HIV dementia, diseases with associated neurofibrillar tangle pathologies and / or dementia pugilistica .

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): C07D403/04A61K31/506A61P25/16A61P25/28A61P3/10C07D401/14C07D405/14
CPCA61K31/506C07D401/14C07D403/04C07D405/14C07D409/14A61P25/00A61P25/16A61P25/28A61P3/10
Inventor 拉斯·安德森欧万·阿泽尔斯蒂芬·伯格杰里米·伯罗斯斯文·赫尔伯格费尔南多·许尔塔托本·佩德森托拜厄斯·赖因迪迪尔·罗蒂西卡林·斯塔夫多米尼卡·图雷克
Owner ASTRAZENECA AB
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