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Benzoxazepin compounds selective for pi3k p110 delta and methods of use

A compound, the technology of C1-C12, is applied in the field of diagnosing or treating mammalian cells or related pathological diseases, and compounds that inhibit the activity of PI3 kinase, and can solve the problems of B cell proliferation, signal transduction loss, and signal transduction damage.

Active Publication Date: 2014-02-05
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Deletion of the PI3Kδ gene or selective introduction of catalytically inactive mutants of PI3Kδ results in an almost complete absence of B cell proliferation and signaling and also results in impaired signaling through T cells

Method used

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  • Benzoxazepin compounds selective for pi3k p110 delta and methods of use
  • Benzoxazepin compounds selective for pi3k p110 delta and methods of use
  • Benzoxazepin compounds selective for pi3k p110 delta and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0527] Example 1 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazepine Heterobenzo[e]azulene-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol

[0528]

[0529] Step 1: Methyl 2-(4-mercaptopiperidin-1-yl)-2-methylpropanoate

[0530]

[0531] H 2 S gas was bubbled through a solution of methyl 2-methyl-2-(4-oxopiperidin-1-yl)propanoate (1.28 g, 6.42 mmol) in isopropanol (13 mL) for 10 min. The reaction mixture was then closed and stirred at RT for 18 h, followed by standing at RT for 8 days. After this time, nitrogen was bubbled through the solution for 10 min, and then NaBH was added 4 (364 mg, 9.63 mmol). The reaction mixture was stirred at RT for 10 min, then heated at 80 °C for 2 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was partitioned between diethyl ether and water. The aqueous layer was further extracted with ether, and the combined organic phases were washed with water, then b...

Embodiment 2

[0536] Example 2 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperidin-4-ylsulfanyl)-4,5-dihydro-6-oxo Hetero-1,3a-diazabenzo[e]azulene

[0537]

[0538] Step 1: 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazepine Heterobenzo[e]azulene-9-ylsulfanyl]piperidine-1-carboxylate tert-butyl ester

[0539]

[0540] 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1, 3a-diazabenzo[e]azulene (100mg, 0.267mmol), tert-butyl 4-mercaptopiperidine-1-carboxylate (87mg, 0.401mmol), Pd 2 (dba) 3 (13 mg, 5 mol%), XantPhos (15 mg, 10 mol%) and DIPEA (0.19 mL) in dioxane (3 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. Using 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazepine Benzo[e]azulene (400mg, 1.068mmol), tert-butyl 4-mercaptopiperidine-1-carboxylate (348mg, 1.604mmol), Pd 2 (dba) 3 (50 mg, 5 mol%), a mixture of XantPhos (61 mg, 10 mol%) and DIPEA (0.745 mL) in dioxa...

Embodiment 3

[0545] Example 3 2-Methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-ylsulfane Base) piperidin-1-yl] propan-1-ol

[0546]

[0547] Step 1: 9-Bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene

[0548]

[0549] 9-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200mg, 0.512mmol), 2-tributylstannylpyridine (226g , 0.614mmol), Pd 2 (PPh 3 ) 2 Cl 2 (36 mg, 0.05 mmol) and copper iodide (29 mg, 0.15 mmol) in DMF (4 mL) was purged with nitrogen, then heated at 100 °C for 1 h using microwave irradiation. The reaction mixture was diluted with MeOH (20 mL), then loaded into SCX-2 cartridge, which was washed with MeOH, and the product was washed with 0.5M NH 3 / MeOH elution. Fractions containing product were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in DCM, then Si-PCC, gradient 0-7% MeOH in EtOAc) to provide the title compound as a cream soli...

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Abstract

Benzoxazepin Formula I compounds, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological disorders, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Description

field of invention [0001] The present invention relates generally to compounds useful in the treatment of disorders mediated by lipid kinases, such as inflammation, immunological disorders and cancer, and more particularly to compounds that inhibit the activity of PI3 kinase. The present invention also relates to methods of using the compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells or associated pathological conditions. Background of the invention [0002] Phosphatidylinositol (PI) is a phospholipid found in cell membranes that plays an important role in intracellular signal transduction. Cell signaling via 3'-phosphorylated phosphoinositides has been implicated in a variety of cellular processes such as malignant transformation, growth factor signaling, inflammation and immunity (Rameh et al. (1999) J. Biol Chem, 274:8347 -8350). The enzyme responsible for the production of these phosphorylated signaling products, phosphatidylinositol ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04C07D498/14C07D519/00A61K31/553A61P35/00A61P37/00A61P19/00A61P31/12A61P5/00A61P3/00A61P25/00
CPCC07D519/00C07D498/04C07D498/14A61P1/00A61P1/04A61P3/00A61P5/00A61P7/00A61P7/04A61P9/00A61P11/00A61P11/06A61P17/00A61P17/06A61P19/00A61P19/02A61P25/00A61P29/00A61P31/12A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61K31/553
Inventor R·埃利奥特E·甘西亚R·海尔德T·赫夫龙B·萨菲纳E·M·苏厄德S·施塔本D·P·萨瑟琳B·瓦什考伊茨魏斌清
Owner F HOFFMANN LA ROCHE & CO AG
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