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Substituted hetero-azepinones

A technology of compounds and heterocycles, applied in organic chemistry, drug combinations, medical preparations containing active ingredients, etc.

Inactive Publication Date: 2015-03-25
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of small molecules to target the Bir2 region of IAPs (including XIAP) has been poorly studied

Method used

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  • Substituted hetero-azepinones

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0568] Preparation of intermediates

[0569] (S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-ylcarbamate tert-butyl ester

[0570]

[0571] Step 1: To a suspension of NaH (60% in mineral oil, 2.88 g, 72 mmol) in DMF (25 mL) at 0 °C was added (S)-2-(tert-butoxycarbonylamino)-3- A solution of hydroxypropionic acid (7 g, 34 mmol) in DMF (25 mL). After 2 hours, a solution of 1-fluoro-2-nitrobenzene (5.29 g, 37.5 mmol) in DMF (25 mL) was added, and the resulting mixture was stirred at 0 °C for 3 hours. Pour the mixture into ice / H 2 O (200 mL), acidified to pH 5.0 with 1 N HCl, extracted with EtOAc. The combined extracts were subjected to Na 2 SO 4 Drying, concentration and purification by flash chromatography gave (S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenoxy)-propionic acid (10.9 g, 97%).

[0572] Step 2: Combine (S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenoxy)-propionic acid (7.6g, 23.3mmol, 1eq) and 10% Pd / C (496mg ) in MeOH (215 mL) was hydrogenated at 1...

Embodiment 1

[0777] (2S)-N-(5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-(3S)-4-oxo-4,5-dihydro-3H-spiro[ Benzo[b][1,4]oxazepine -2,1'-cyclohexane]-3-yl)-2-(methylamino)propionamide hydrochloride

[0778]

[0779] Step 1: Methyl-(tert-butyl)-(2S)-1-oxo-1-((3S)-(4-oxo-2′,3′,4,5,5′,6′ -Hexahydro-3H-spiro[benzo[b][1,4]oxazepine -2,1'-cyclohexane]-3-ylamino))propan-2-ylcarbamate (44.1mg, 102μmol, Eq: 1.00), 6-bromo-1-(chloromethyl)-2 - Methoxynaphthalene (43.8 mg, 153 μmol, Eq: 1.5), NaI (23.0 mg, 153 μmol, Eq: 1.5) and Cs 2 CO 3 (49.9 mg, 153 μmol, Eq: 1.5) in DMF (2 mL) was heated to 65°C. After 18 h the mixture was diluted with EtOAc, washed with saturated NaCl, washed with NaCl 2 SO 4 Dried and concentrated. The residue was purified by flash chromatography to afford (2S)-1-(5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-(3S)-4-oxo-4, 5-Dihydro-3H-spiro[benzo[b][1,4]oxazepine - tert-butyl 2,1'-cyclohexane]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (33.7 mg, 48%) as a white ...

Embodiment 2

[0790] 6-methoxy-5-(((S)-3-((S)-2-(methylamino)propionamido)-4-oxo-2',3',5',6'- Tetrahydro-3H-spiro[benzo[b][1,4]oxazepine -2,4'-pyran]-5(4H)-yl)methyl)-2-naphthoic acid trifluoroacetate

[0791]

[0792] Step 1: Adding (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2′,3′,4 , 5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine -2,4'-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate tert-butyl ester (0.17g, 249μmol, Eq: 1.00), Pd(OAc) 2 (2.24 mg, 9.96 μmol, Eq: 0.04) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (11.5 mg, 19.9 μmol, Eq: 0.08) in 5mL microwave tube, the tube was evacuated and filled with N 2 . MeOH (79.8 mg, 101 μl, 2.49 mmol, Eq: 10) and TEA (0.5 mL) were added, the tube was filled with CO gas for about 30 seconds, and placed in an oil bath to heat to 70°C. After 18 h, the mixture was cooled, diluted with EtOAc, washed with 1N HCl, H 2 O and washed with saturated brine. The organic mixture was subjected to Na 2 SO ...

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Abstract

There are provided compounds of the formula (1) wherein W, X, Y, Z, R1, R2, R3, R4, R5 and R6 are described herein. These compounds are useful for the treatment of proliferative diseases, including cancer.

Description

field of invention [0001] The present invention relates to substituted hetero-aza Ketones and their use for inhibiting the binding of SMAC protein to inhibitor of apoptosis protein (IAP) and / or inhibiting the binding of activated caspase protein to IAP for the treatment of human diseases such as cancer. Background of the invention [0002] Cancer is a disease in which uncontrolled cell growth leads to local expansion of tumors and possibly distant metastasis. One mechanism by which cancer cells grow is by avoiding apoptosis (also known as programmed cell death). Alterations in apoptotic pathways have been linked to cancer cell resistance to standard treatments, such as chemotherapy or radiation, and to cancer initiation and progression. [0003] The two basic pathways of apoptotic cell death are the intrinsic pathway and the extrinsic pathway. The intrinsic apoptotic pathway can be initiated by a variety of mechanisms including cellular stress, drug-induced damage or DNA...

Claims

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Application Information

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IPC IPC(8): C07D267/14C07D498/10C07D281/10A61K31/553A61K31/554
CPCC07D267/14C07D281/10C07D498/10A61P35/00A61P43/00C07D267/12C07D413/06C07D413/12C07D413/14C07D417/06C07D417/12A61K31/553A61K31/554
Inventor A·F·唐奈X·韩R·F·凯斯特N·康K·乐Y·楼C·米乔德J·A·莫里特尼S·雷米泽夫斯基K·C·鲁帕特W·允
Owner F HOFFMANN LA ROCHE & CO AG
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