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Indane amine derivative, and preparation method and application thereof

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

Pending Publication Date: 2022-04-12
CONVALIFE SHANGHAI 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

[0160] Example 1: N-hydroxy-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carboxamide

[0161]

[0162] Step 1: Synthesis of ethyl 2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carboxylate

[0163] Ethyl 2-chloropyrimidine-5-carboxylate (200mg, 1.07mmol) and 1-aminoindan (214mg, 1.61mmol) were dissolved in 1,4-dioxane (3ml). Under ice-cooling, triethylamine (326 mg, 3.22 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 (174 mg, yield 57.3%, white solid). LC-MS(ESI)m / z[M+H] + 284.2.

[0164] Step 2: Synthesis of N-hydroxy-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carboxamide

[0165] Dissolve ethyl 2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carboxylate (100mg...

Embodiment 2

[0166] Example 2: N-Hydroxy-2-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)pyrimidine-5-carboxamide

[0167]

[0168] Step 1: Synthesis of ethyl 2-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)pyrimidine-5-carboxylate

[0169] Ethyl 2-chloropyrimidine-5-carboxylate (100mg, 0.537mmol), 1,2,3,4-tetralin-1-amine (79.0mg, 0.537mmol) and potassium carbonate (222mg, 1.612mmol) Add to N,N-dimethylformamide (1 ml). The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was lowered to room temperature, diluted with water (20ml), extracted with dichloromethane (30ml╳2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (136mg, crude product, yellow solid ), used directly in the next reaction without further purification. LC-MS(ESI)m / z[M+H] + 298.2.

[0170] Step 2: Synthesis of N-hydroxy-2-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)pyrimidine-5-carboxa...

Embodiment 3

[0172] Example 3; N-Hydroxy-2-(chroman-4-yl-amino)pyrimidine-5-carboxamide

[0173]

[0174] Step 1: Synthesis of ethyl 2-(chroman-4-yl-amino)pyrimidine-5-carboxylate

[0175] 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.

[0176] Step 2: Synthesis of N-hydroxy-2-(chroman-4-yl-amino)pyrimidine-5-carboxamide

[0177] Dissolve ethyl 2-(chroman-4-yl-amino)pyrimidine-5-carboxylate (130mg, 0.435mmol) in a mixed solvent of methanol and dichloromethane (13ml...

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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 the inhibitory activity on HDAC6, has better selectivity on HDAC1, HDAC3 or HDAC8, and is good in 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 (histone 0.1% diethylamine (DEA) cetylases, HDACs) are important functional proteins of epigenetic regulation , has attracted widespread attention of scientists in recent decades. 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, ...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D405/12A61K31/506A61P35/00A61P37/02A61P19/02A61P29/00A61P25/02A61P11/06
Inventor 程耀邦王永辉董志强沈孝坤栗增
Owner CONVALIFE SHANGHAI CO LTD