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Benzoindole bifunctional molecular derivatives as well as preparation method and application thereof

A bifunctional molecule, benzindole technology, applied in the bifunctional molecular derivatives of benzindole and its preparation, as a BET protein inhibitor degradation agent, can solve the problem of poor patient tolerance, single structure, compound PK properties and poor in vitro properties, etc., to achieve high-efficiency induction of apoptosis, good protein affinity and selectivity, and good application prospects

Pending Publication Date: 2020-12-25
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above types of inhibitors are relatively simple in structure and have no selectivity for BET Brmodomain. At the same time, the PK properties and in vitro properties of the compounds are poor. At the same time, in clinical trials, this type of non-selective pan-BET has high-dose patient tolerance Poor, had to reduce the dose at the expense of efficacy, generally speaking, pan-BET inhibitors suffered a certain amount of trauma in both preliminary research and clinical trials

Method used

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  • Benzoindole bifunctional molecular derivatives as well as preparation method and application thereof
  • Benzoindole bifunctional molecular derivatives as well as preparation method and application thereof
  • Benzoindole bifunctional molecular derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] 3-(6-((2-methoxyphenyl)sulfonylamino)-1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)propanoic acid (I-1g)

[0104]

[0105] Step 1: 5-Bromo-1H,3H-benzo[de]isochromene-1,3-dione (I-1a)

[0106] Add 1,8-naphthalene dicarboxylic anhydride (10.0g, 50.5mmol) and silver sulfate (7.9g, 25.25mmol, 0.50equiv) into concentrated sulfuric acid (200mL) solution, stir at room temperature for 30 minutes, then add liquid bromine ( 3.2mL, 63.0mmol, 1.26equiv), heated to 60°C, heated for 8-10 hours, then cooled to 20°C. The completion of the reaction was checked by TLC, and the silver bromide by-product solid was filtered off to obtain a clear orange solution. The orange solution was added dropwise to an ice-water mixture (1 L), stirred at room temperature for 20 min, and an off-white solid was obtained by filtration. The filter cake was washed with water (50mL), then washed with cold ethanol (100mL×2), and dried in a constant temperature vacuum oven at 60°C to obtain a white solid ...

Embodiment 2

[0120] N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethyl)-3-(6 -((2-Methoxyphenyl)sulfonylamino)-1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)propionamide (Ⅱ-1 )

[0121]

[0122] Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (Ⅱ-1a)

[0123] Weigh 4-fluoroisobenzofuran-1,3-dione (2g, 12.04mmol, 1equiv) into an eggplant-shaped bottle, dissolve it with 20mL AcOH, add 3-aminopiperidine-2,6-dione hydrochloride Salt (2.18 g, 13.24 mmol, 1.1 equiv) and AcOK (2.36 g, 24.08 mmol, 2 equiv). Stir and heat at 60°C for 12 hours. TLC detected that the reaction was complete, extracted with EA, washed the organic layer with saturated brine, Mg 2 SO 4 After drying, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography to obtain a white solid (II-1a) (2.13 g, 7.71 mmol), yield: 64%. MS m / s(ESI)[M+H]+ : 277.1.

[0124] Step 2: tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino...

Embodiment 3

[0131] N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)propyl)-3-(6 -((2-methoxyphenyl)sulfonylamino)-1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)propionamide (Ⅱ-2 )

[0132]

[0133] Step 1: tert-Butyl (3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)propyl)carbamate Esters (Ⅱ-2a)

[0134] Its preparation method is the same as Step 2 of Example 2: (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino) The preparation of ethyl) tert-butyl carbamate (Ⅱ-1b) is similar to 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione ( II-1a) was used as the raw material, and the dosage was 300mg (1.09mmol). Finally, a light yellow solid (II-2a) (182mg, 0.42mmol) was obtained, with a yield of 39%.

[0135] Step 2: 4-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Ⅱ-2b) .

[0136] Step 3: N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)propyl)-3 -(6-((2-methoxyphenyl)sulfonylamino)-1-methyl-2-oxo-1,...

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Abstract

The invention belongs to the field of medical chemistry, and particularly relates to benzoindole bifunctional molecule derivatives as well as a preparation method and application thereof. The benzoindole bifunctional molecule of the derivative, or tautomer, mesomer, raceme, enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt has a structure as shown in a general formula (I). Thederivative is a protein degradation targeting chimeric body (PROTACs) technology, and can induce the degradation of BET protein. The invention also discloses application of the bifunctional molecularcompound in medicines for preventing and / or treating BET protein related diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a benzindole bifunctional molecular derivative and its preparation method and application, especially its use as a BET protein inhibitor and degradation agent. Background technique [0002] Tumor is one of the main causes of human death worldwide. Generally speaking, the current five-year survival rate of tumors is low, and the early detection and cure of tumors are very difficult. The current kinase anti-tumor drugs have gone through the explosive period of rapid research and development. Due to the limitations of their own targets and the characteristics of targets in There are many problems in drug development, such as drug resistance and safety risks brought by multiple potential targets. Therefore, the development of new treatment methods has important clinical value and research significance in the prevention, treatment and treatment of tumors, and realizes the prevention...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/454A61P35/00A61P35/02A61P29/00A61P19/02
CPCA61P19/02A61P29/00A61P35/00A61P35/02C07D401/14
Inventor 陆涛陈亚东姜飞李红玫李慧丽
Owner CHINA PHARM UNIV
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