Indane amine derivative, and preparation method and application thereof

A technology of indane amine and compound, which is applied in the field of indane amine derivatives, can solve the problems of inconvenience in clinical use, poor cell metabolism and the like, and achieves the effects of good inhibitory activity, good selectivity and good metabolic stability

Pending Publication Date: 2022-04-22
SHANGHAI LITEDD CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, the cell metabolism of ACY-1215 and ACY-241 is relatively poor and its half-life in human trials shows that the half-life is only 3 hours, which brings a lot of inconvenience to clinical use

Method used

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  • Indane amine derivative, and preparation method and application thereof
  • Indane amine derivative, and preparation method and application thereof
  • Indane amine derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] Example 1: N-(7-(hydroxylamino)-7-oxoheptyl)-2-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)pyrimidine-5-carboxamide

[0175]

[0176] Step 1: Synthesis of ethyl 2-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)pyrimidine-5-carboxylate

[0177] Dissolve ethyl 2-chloropyrimidine-5-carboxylate (300mg, 1.61mmol) in N,N-dimethylformamide (5ml), add 1,2,3,4-tetrahydronaphthalene-1-amine (237mg, 1.61mmol) and potassium carbonate (666mg, 4.83mmol). The reaction mixture was stirred at 80°C for 3 hours. The reaction was cooled to room temperature, the mixture was poured into water (50ml), the precipitated solid was filtered, the filter cake was washed with water (20ml), and the filter cake was dried under reduced pressure to obtain the target compound (490mg, crude product, yellow solid). LC-MS(ESI)m / z[M+H] + 298.2.

[0178] Step 2: Synthesis of 2-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)pyrimidine-5-carboxylic acid

[0179] Dissolve ethyl 2-((1,2,3,4-tetrahydronaphthalen-1-yl)...

Embodiment 2

[0184] Example 2: N-(7-hydroxylamino-7-oxoheptyl)-2-(chroman-4-ylamino)pyrimidine-5-carboxamide

[0185]

[0186] Step 1: Synthesis of ethyl 2-(chroman-4-yl-amino)pyrimidine-5-carboxylate

[0187] Ethyl 2-chloropyrimidine-5-carboxylate (200mg, 1.08mmol) and chroman-4-ylamine (240mg, 1.61mmol) were dissolved in 1,4-dioxane (5ml) , triethylamine (326 mg, 3.23 mmol) was added dropwise to the reaction mixture. After the dropwise addition, the reaction mixture was stirred at room temperature for 2 hours. The organic solvent was removed by concentration under reduced pressure, and methanol (2 ml) was added. After filtration, the filter cake was dried under reduced pressure to obtain the target compound (265 mg, yield 82.1%, white solid). LC-MS(ESI)m / z[M+H] + 300.1.

[0188] Step 2: Synthesis of 2-(chroman-4-ylamino)pyrimidine-5-carboxylic acid

[0189] Dissolve ethyl 2-(chroman-4-ylamino)pyrimidine-5-carboxylate (150mg, 0.501mmol) in a mixed solvent of tetrahydrofuran (3ml)...

Embodiment 3

[0194] Example 3: N-(7-(hydroxylamino)-7-oxoheptyl)-2-(isochroman-4-ylamino)pyrimidine-5-carboxamide

[0195]

[0196] Step 1: Synthesis of 1-((allyloxy)methyl)-2-iodobenzene

[0197] Sodium hydride (60%, 1.15g, 28.8mmol) was added to tetrahydrofuran (100ml), and (2-iodophenyl)methanol (4.5g, 19.2mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for half After hours 3-bromoprop-1-ene (2.53 g, 21.1 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature. Water (50ml) was added to the reaction mixture at 0°C, and extracted with ethyl acetate (100ml×3). The combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation and purification by column chromatography (silica gel; petroleum ether: ethyl acetate = 20:1-5:1) gave the target compound (4.50 ...

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Abstract

The invention discloses a dihydroindene amine derivative as well as a preparation method and application thereof. The invention provides a dihydroindene amine compound as shown in a formula I or a pharmaceutically acceptable salt thereof. The compound provided by the invention has good inhibitory activity on HDAC6, has good selectivity on HDAC1 and / or HDAC3, and has good metabolic stability.

Description

technical field [0001] The invention relates to an indane amine derivative, its preparation method and application. Background technique [0002] Epigenetic modification plays a very important role in the process of gene expression regulation, and histone deacetylases (HDACs), as an important functional protein of epigenetic regulation, have attracted scientists in recent decades widespread attention. On the one hand, HDACs can mediate the deacetylation of histone substrate lysine, which is conducive to the formation of a more compact structure of chromatin, and some HDACs can interact with other chromatin regulatory proteins to form co-repression complexes, Thus regulating gene expression, cell cycle and cell differentiation and other life processes; on the other hand, some HDACs can also catalyze the deacetylation of non-histone substrate lysine, thus playing an important role in more cell regulatory pathways ( Nat Biotechnol, 2015, 10.1038 / nbt.3130; Int J Cancer, 2019, ...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D405/12A61K31/506A61K31/505A61P35/00A61P35/02A61P19/02A61P19/08A61P17/06A61P9/10A61P1/00A61P11/00A61P11/06A61P13/12A61P7/06A61P7/00A61P29/00A61P37/06A61P21/04A61P17/00A61P1/16A61P1/12A61P3/10A61P25/02
CPCC07D239/42C07D405/12A61P35/00A61P35/02A61P19/02A61P19/08A61P17/06A61P9/10A61P1/00A61P11/00A61P11/06A61P13/12A61P7/06A61P7/00A61P29/00A61P37/06A61P21/04A61P17/00A61P1/16A61P1/12A61P3/10A61P25/02
Inventor 程耀邦王永辉董志强沈孝坤栗增
Owner SHANGHAI LITEDD CO LTD
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