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Novel benzodiazepine derivatives and uses thereof

A compound, heteroaryl technology, applied in the field of new benzodiazepine derivatives, can solve problems such as low activity

Pending Publication Date: 2021-09-28
INTOCELL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The linker component of an ADC is an important feature for the development of targeted anticancer agents with the desired target specificity, i.e. high activity in tumor cells but low activity in healthy cells

Method used

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  • Novel benzodiazepine derivatives and uses thereof
  • Novel benzodiazepine derivatives and uses thereof
  • Novel benzodiazepine derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0633] Example 1: Preparation of Compound L-1

[0634]

[0635] Preparation of Compound L-1-1

[0636] at -78°C and N 2 To a solution of dimethyl 5-hydroxyisophthalate (5 g, 23.79 mmol) in anhydrous THF (300 mL) was added LAH (3.6 g, 95.15 mmol) dropwise under atmosphere. The reaction mixture was stirred at room temperature for 17 hours. After the reaction was complete, 15% NaOH solution (4 mL), H 2 O (8 mL) and EA (100 mL), then the reaction mixture was stirred for 1 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound L-1-1 (3.02 g, 82%).

[0637] 1 H NMR (400 MHz, DMSO-d6) δ 6.66 (s, 1H), 6.58 (s, 2H), 4.38 (s, 4H).

[0638] Preparation of Compound L-1-2

[0639] in N 2 A solution of compound L-1-1 (2 g, 12.97 mmol) was dissolved in HBr (5.0 mL, 33% in AcOH) under atmosphere. After stirring at 60°C for 18 hours, by adding NaHCO 3 The solution (pH~8) quenched the reaction...

Embodiment 2

[0644] Embodiment 2: the preparation of compound L-2

[0645]

[0646] Preparation of compound L-2-1

[0647] at 0°C and N 2 To a solution of 3,5-pyridinedicarboxylic acid (1.0 g, 5.98 mmol) in anhydrous THF (50 mL) was added boron trifluoride tetrahydrofuran complex (30.0 mL, 30.0 mmol, 1 M THF) under atmosphere . The reaction was allowed to warm to room temperature and stirred for 18 hours. The mixture was quenched with 2N HCl until pH 2, and extracted with distilled water (20 mL) and EA (50 mL x 2). The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by preparative TLC to obtain compound L-2-1 (363 mg, 48%).

[0648] 1 H NMR (400MHz, DMSO-d 6 )δ8.38 (s, 2H), 7.99 (s, 1H), 5.59 (t, J=4.0Hz, 2H), 4.61 (d, J=5.2Hz, 2H).

[0649] Preparation of Compound L-2

[0650] A mixture of L-2-1 (100 mg, 0.72 mmol) and HBr (1.5 mL, 48% in AcOH) was stirred at 120°C for 3 hours. with NaHCO ...

Embodiment 3

[0652] Embodiment 3: the preparation of compound L-3

[0653]

[0654] Preparation of Compound L-3-1

[0655] at room temperature and N 2 Under atmosphere, 4-chloropyridine-hydrochloride (1.0 g, 6.67 mmol) and diethanolamine (1.05 g, 10.00 mmol) were treated with NaOH (1.07 g, 26.67 mmol) in H 2 O (12 mL) and heated to 110 °C for 1 h using a microwave reactor. After the reaction was quenched with distilled water (18 mL) / methanol (10 mL) and extracted with EA (200 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography to obtain compound L-3-1 (160 mg, 13%).

[0656] 1 H NMR (400MHz, DMSO-d6) δ 8.10 (d, J = 5.6Hz, 2H), 6.83 (d, J = 6.0Hz, 2H), 4.91 (br s, 2H), 3.57 (s, 8H). EI-MS m / z:183(M + +1).

[0657] Preparation of Compound L-3

[0658] A mixture of compound L-3-1 (10 mg, 0.05 mmol) and HBr (2.0 mL, 48% in water) was reacted in a microwave at 150°C f...

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Abstract

Disclosed are novel benzodiazepine derivatives and uses thereof. The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof. The compounds, conjugates, and pharmaceutical compositions provided by the present invention can be used to inhibit abnormal cell growth or treat proliferative disorders in mammals, and can also be used to treat mammalian conditions such as cancer, rheumatoid arthritis, multiple sclerosis, graft-versus-host disease (GVHD), transplant rejection, lupus, myositis, infection, immunodeficiency such as AIDS and inflammatory diseases, thereby extending lifespan.

Description

[0001] This application is the PCT international application PCT / IB2019 / 000691 submitted on May 29, 2019. The Chinese patent application number is 201980035084.3 and the invention name is "New Benzodiazepine Derivatives and their uses" is a divisional application of the invention patent application. [0002] related application [0003] This application claims the benefit of U.S. Provisional Application No. 62 / 677,498, filed May 29, 2018, the contents of which are incorporated herein by reference in their entirety. technical field [0004] The application relates to a novel benzodiazepine Derivatives and their uses. Background technique [0005] Antibody-drug conjugates (ADCs) are an emerging class of powerful antitumor drugs that are effective against a variety of cancers. ADCs typically include three distinct features: a cell-binding agent or targeting moiety; a linker; and a cytotoxic agent. The linker component of an ADC is an important feature for the development ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00C07H15/203A61K31/5513A61K31/706A61K45/06A61P35/00
CPCC07D519/00C07H15/203A61K45/06A61P35/00C07D403/12C07H17/02C07D487/04
Inventor T·朴S·H·吴S·金S·朴J·崔D·郑D·徐J·李S·李S·尹H·S·李O·朴B·徐M·薛
Owner INTOCELL INC
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