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Tetrahydrobenzofuro[2,3-c]pyridine and beta-carboline compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates

Pending Publication Date: 2021-02-09
AC IMMUNE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, only one kinase inhibitor, nilotinib, is currently being tested in clinical trials

Method used

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  • Tetrahydrobenzofuro[2,3-c]pyridine and beta-carboline compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates
  • Tetrahydrobenzofuro[2,3-c]pyridine and beta-carboline compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates
  • Tetrahydrobenzofuro[2,3-c]pyridine and beta-carboline compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0200]

[0201] Step A

[0202] Add (4-fluorophenyl)hydrazine HCl-salt (1g, 6.1mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (1.2g, 6.1mmol) in 1,4-dioxane at 0°C (10 mL) was added concentrated H 2 SO 4 (1 mL). The reaction mixture was then heated at 110 °C for 3 h. The reaction mixture was cooled to 25°C and the precipitate was filtered off. The solid was dissolved in water basified with NaOH solution, extracted with dichloromethane, the organic phase was separated and washed with NaOH 2 SO 4 Drying, filtration and removal of solvent under reduced pressure afforded the cyclized title compound as a light yellow solid (0.6 g, 54%). 1 H-NMR (400MHz, DMSO-d 6 )δ=10.73(br-s,1H),7.21-7.22(m,1H),7.06-7.07(m,1H),6.78-6.79(m,1H),3.83(s,2H),2.94-2.95( m,2H),2.49-2.50(m,2H).MS: 191(M+H) + .

[0203] Step B

[0204] To a solution of the title compound from Step A above (0.6 g, 3.15 mmol) in THF (10 mL) was added triethylamine (1.3 mL, 9.47 mmol) and di-tert-butyl d...

preparation example 2

[0213]

[0214] Step A

[0215] To a solution of the title compound from Preparation 1, Step B (0.55 g, 1.89 mmol) in THF (5 mL) was added sodium hydride (0.136 g, 5.6 mmol) followed by p-toluenesulfonyl chloride (0.396 g, 2.07 mmol) . The reaction mixture was stirred at room temperature for 30 minutes. The mixture was dissolved in ethyl acetate (20 mL), washed with water and brine. Separate the organic phase with Na 2 SO 4 Dry, filter and remove the solvent under reduced pressure. The crude reaction mixture was purified by flash column chromatography using hexane / ethyl acetate (70:30) to afford the title compound (0.4 g, 47%).

[0216] 1 H-NMR (400MHz, DMSO-d 6 )δ=8.00(s,1H),7.77(s,2H),7.30-7.32(m,3H), 7.16-7.18(m,1H),4.87(s,2H),3.64(s,2H),2.62 (br-s,2H),2.32(s,3H),1.39(s,9H).MS:445.2(M+H) + .

[0217] Step B

[0218] To a solution of the title compound from Step A above (0.4 g, 0.9 mmol) in dichloromethane (10 mL) was added 2N HCl (5 mL) in 1,4-dioxane. Th...

preparation example 3

[0220]

[0221] Step A

[0222] Add (4-methoxyphenyl)hydrazine HCl-salt (10g, 57.5mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (11.4g, 57.5mmol) at 0°C in 1,4-bis Concentrated H was added to a solution in oxane (100 mL) 2 SO 4 (10 mL). The reaction mixture was then heated at 110 °C for 3 h. The reaction mixture was cooled to 25°C and the precipitate was filtered off. The solid was dissolved in water basified with NaOH solution and extracted with dichloromethane. Separate the organic phase with Na 2 SO 4 Drying, filtration and removal of solvent under reduced pressure afforded the cyclized title compound as a brown gummy solid (10 g, crude). The product was used as such in the next step. MS:203.2(M+H) + .

[0223] Step B

[0224] To a solution of the title compound from Step A above (10 g, 49.5 mmol) in THF (10 mL) was added triethylamine (20 mL, 148.5 mmol) and di-tert-butyl dicarbonate (11.8 g, 54 mmol) and the reaction The mixture was stirred for 12h...

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Abstract

The present invention relates to novel compounds of formula (I) that can be employed in the treatment, alleviation or prevention of a group of disorders and abnormalities associated with Tau (Tubulinassociated unit) protein aggregates including, but not limited to, Neurofibrillary Tangles (NFTs), such as Alzheimer's disease (AD).

Description

[0001] field of invention [0002] The present invention relates to novel compounds useful for the treatment, amelioration or prevention of a group of conditions and abnormalities associated with aggregates of the Tau (tubulin-associated unit) protein, including but not limited to neurofibrillary tangles (NFT) , such as Alzheimer's disease (AD). [0003] Background of the invention [0004] Many diseases of aging are based on or involve extracellular or intracellular deposits of amyloid or amyloid-like proteins, which contribute to disease pathogenesis as well as disease progression. The most characterized amyloid that forms extracellular aggregates is amyloid beta (Aβ). Other examples of amyloid proteins that form extracellular aggregates are prions, ATTR (transthyretin) or ADan (ADanPP). Amyloid-like proteins that primarily form intracellular aggregates include, but are not limited to, Tau, α-synuclein, TAR DNA binding protein 43 (TDP-43) and huntingtin (htt). Diseases inv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D471/14C07D519/00A61P25/00A61K31/437A61K31/444A61K31/496
CPCC07D471/04C07D471/14C07D519/00A61P25/00A61K31/5377A61K31/437A61P25/28C07D513/04A61K31/145A61K31/185A61K31/27A61K31/444A61K31/445A61K31/473A61K31/496A61K31/497A61K31/501A61K31/5386A61K31/55A61K31/5513A61K45/06C07D471/18
Inventor S·纳帕利E·加贝列里J·莫丽特
Owner AC IMMUNE SA
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