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Novel azepane derivatives

A technology of heterocyclic groups and alkyl groups, applied in the field of preparing the azepane derivatives, can solve the problems of unreported small molecule inhibitors of AKT1

Inactive Publication Date: 2005-07-13
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

No small molecule inhibitors of AKT1 reported in the literature

Method used

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Examples

Experimental program
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Effect test

Embodiment 1a

[0096] N-{(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]azepan-3-yl}- Isonicotinamide hydrochloride (1a)

[0097] 0.05 g of 1b was dissolved in 2 ml of hydrochloric acid in dioxane (4M) at room temperature and stirred for 24 hours. The solvent was evaporated in vacuo and the residue was redissolved in methanol and evaporated to dryness three times, yielding 0.038 g (82%) of 1a as pale yellow crystals. MS (ESI): m / z (%): 507 (MH + ), 505 ([M-H] + ). Mp.200-222°C.

Embodiment 1b

[0099] (3R, 4R)-4-[4-(2-fluoro-6-methoxymethoxy-3-methoxy-benzoyl)-benzoylamino]-3-[(pyridine-4- Carbonyl)-amino]-azepane-1-carboxylate tert-butyl ester (1b)

[0100] Dissolve 0.167 g of 1c in 5 mL of CH at room temperature 2 Cl 2 middle. 0.167 g of 4-(2-fluoro-3-methoxy-6-methoxymethoxy-benzoyl)-benzoic acid (1d), 0.031 g of 4-dimethylaminopyridine, and 0.113 g of DCC were added. The reaction mixture was stirred at room temperature for 5 hours. The precipitate was filtered off and washed with CH 2 Cl 2 washing. The residue was evaporated in vacuo to yield 0.46 g of crude product. Column chromatography (SiO 2 , pentane / ethyl acetate 1:10) afforded 0.248 g (76%) of 1b as white crystals. M.p.106°C; MS (ESI): m / z (%): 651 (MH + ), 649 ([M-H] + .

Embodiment 1c

[0102] (3R,4R)-4-Amino-3-[(pyridine-4-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester (1c)

[0103] 5.5 g of 1e was dissolved in 135 mL of THF and 15 mL of ethanol, and 1 g of Pd / C (10%) was added. The reaction mixture was hydrogenated at 1 bar for 8 hours. After filtration, the residue was evaporated in vacuo to yield 4.6 g (90%) of 1c as a light brown powder. MS (ESI): m / z (%): 335 (MH + ), 333 ([M-H] + ).

[0104] The synthesis of 1d(4-(2-fluoro-3-methoxy-6-methoxymethoxy-benzoyl)-benzoic acid) is described in EP0663 393A1.

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PUM

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Abstract

The present invention provides novel azepane derivatives or pharmaceutically acceptable salts thereof according to the general formula (I) and their preparation methods, wherein the remaining symbols have the meanings given in the description. The compounds according to the invention have anti-proliferative activity and show increased plasma stability.

Description

[0001] The present invention relates to novel azepane derivatives, or pharmaceutically acceptable salts thereof, which have anti-cell proliferative activity, such as anticancer activity, and are therefore useful in methods of treatment of the human or animal body. The invention also relates to processes for the preparation of said azepane derivatives, pharmaceutical compositions comprising them and their use in the preparation of medicaments for producing an anti-cell proliferative effect in warm-blooded animals such as humans. Background technique [0002] Cell signaling pathways regulate cell growth, proliferation, and apoptosis. Kinases transduce signals of cell growth or apoptosis through the phosphorylation of their substrates, most of which are downstream kinases themselves involved in cell signaling processes. Regulates kinase activity through phosphorylation and dephosphorylation that affect kinase conformational changes. Overexpression or constitutive activation of k...

Claims

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Application Information

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IPC IPC(8): A61K31/55A61P35/00A61P43/00C07D223/12C07D401/12C07D401/14C07D403/12C07D405/14
CPCC07D223/12C07D401/12C07D401/14C07D403/12C07D405/14A61P35/00A61P43/00
Inventor W-G·弗里贝B·马斯宙斯特R·舒马赫
Owner F HOFFMANN LA ROCHE & CO AG
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