Inhibitors of Akt activity

A technology selected from, cycloalkyl, applied in the direction of organic active ingredients, medical preparations containing active ingredients, biocides, etc.

Inactive Publication Date: 2006-11-08
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The regulatory site for phosphorylation of upstream kinases near the carboxyl terminus of Akt / PKB has not been identified, but recent reports implicate the role of integrin-binding kinase (ILK-1), a serine / threonine protein kinase, or autophosphorylation. Chemicalization

Method used

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Examples

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preparation example Construction

[0474] In the preparation of the compound of formula (II) of the present invention, the following novel intermediates were prepared.

[0475] 4-(7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine, which is Intermediate that can be prepared in Example 18(e).

[0476] 2-(4-amino-1,2,5-oxadiazol-3-yl)-1-methyl-4-phenyl-1H-imidazo[4,5-c]pyridine-7-carboxylic acid, It is an intermediate that can be prepared in Example 98(g).

[0477] In the preparation of the compounds of formula (I) of the present invention, the following novel intermediates were prepared.

[0478] Ethyl 4-chloro-5-nitro-6-phenyl-3-pyridinecarboxylate, an intermediate that could be prepared in Example 98(d).

[0479] The present invention also relates to a method for preparing a compound of formula (I) and / or pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, the method comprising 4-chloro-5-nitro-6-phenyl- Ethyl 3-pyridinecarboxylate is converted to a comp...

Embodiment 1

[0574] Preparation of 4-(4-phenyl-1-piperidin-4-yl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine trifluoroacetate

[0575] a) (1-benzyl-piperidin-4-yl)-(3-nitro-pyridin-4-yl)-amine

[0576] 4-Methoxy-3-nitropyridine (4.34g, 28.1mmol), 4-amino-1-benzylpiperidine (6.01g, 30.9mmol), and NaOAc (2.31g, 28.1mmol) were dissolved in anhydrous The mixture in ethanol (20 mL) was stirred at reflux for 54 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Dissolve the residue in CH 2 Cl 2 (100 mL) and washed with water (2×30 mL). The organic layer was passed through anhydrous MgSO 4 Drying and concentration in vacuo gave the product (8.78g) as a dark yellow solid. 1 H NMR (400MHz, CDCl 3 )δ9.21 (s, 1H), 8.26 (dd, J=6.0, 0.4Hz, 1H), 8.20 (wide d, J=7.1Hz, 1H), 7.34-7.25 (complex m, 5H), 6.70 ( d, J=6.0Hz, 1H), 3.62-3.53(m, 1H), 3.55(s, 2H), 2.89-2.79(m, 2H), 2.30-2.20(m, 2H), 2.10-2.00(m, 2H), 1.76-1.65 (m, 2H).

[0577] b)N 4 -(1-Benzyl-...

Embodiment 2

[0588] 4-[4-(3-Chloro-phenyl)-1-piperidin-4-yl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine hydrochloride salt preparation

[0589] By substituting 3-chlorophenylboronic acid for the phenylboronic acid in Example 1(d) and the method described in Examples 1(e) to 1(f), and trituration with 4N HCl / dioxane , to give the title compound. MS(ES+)m / z 396.0[M+H] + .

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Abstract

Invented are novel 1 H-imidazo[4,5-c]pyridin-2-yI compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.

Description

technical field [0001] The present invention relates to novel 1H-imidazo[4,5-c]pyridin-2-yl compounds as inhibitors of protein kinase B (hereinafter PKB / Akt, PKB or Akt) activity and in cancer and joint Use in the treatment of inflammation. Background technique [0002] The present invention relates to 1H-imidazo[4,5-c]pyridin-2-yl containing compounds which are one or more isoforms of the serine / threonine kinase Akt (also known as protein kinase B) (isoform) activity inhibitors. The invention also relates to pharmaceutical compositions comprising the compound and methods of using the compound to treat cancer and arthritis (Liu et al. Current Opin. Pharmacology 3 : 317-22 (2003)). [0003] Apoptosis (programmed cell death) plays an important role in embryonic development and the pathogenesis of various diseases such as neurodegenerative diseases, cardiovascular diseases and cancer. Recent work has turned to the identification of various pro- and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4965A01N43/42A01N43/54A61K31/44A61K31/505C07D401/00C07D403/00C07D405/00C07D409/00
Inventor 德克·A·希尔丁塔米·J·克拉克戴维·H·德鲁里杰克·D·莱伯艾戈·萨福诺夫丹尼斯·S·亚马希塔
Owner SMITHKLINE BECKMAN CORP
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