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Histone demethylase LSD1 (lysine specific demethylase 1) inhibitor

An aryl and hydroxyl technology, which is applied in the field of histone lysine demethylase LSD1 inhibitors, can solve the problems that LSD2 cannot be found, proteins cannot form complexes, etc.

Active Publication Date: 2017-09-19
福建金乐医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

LSD2 is similar to LSD1. With the participation of FAD, it can specifically remove the monomethyl and dimethyl modifications of H3K4 in vitro. However, the difference between LSD2 and LSD1 in biology is that in vitro, LSD2 cannot form complexes with CoREST and other proteins. LSD2 has not been found so far in any protein complex containing LSD1 (Yang, Z.; et al. Cell. Res 2010,20(3), 276-287)

Method used

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  • Histone demethylase LSD1 (lysine specific demethylase 1) inhibitor
  • Histone demethylase LSD1 (lysine specific demethylase 1) inhibitor
  • Histone demethylase LSD1 (lysine specific demethylase 1) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] The preparation of the derivative (compound-1) shown in embodiment 1 general formula (I)

[0082] 4-((R)-3-phenyl-4-(((R)-1-propylpyrrolin-2-yl)methylene)piperazin-1-yl)phenol (hereinafter referred to as compound 1) preparation

[0083]

[0084] Compound-1

[0085] This compound can be prepared by the following steps:

[0086]

[0087] 1.1 Preparation of (R)-2-(2-(benzyloxycarbonylamino)acetamido)-2-phenylacetic acid methyl ester (1-2)

[0088]

[0089] 2-Benzyloxycarbonylaminoacetic acid (1-1) (2.98 g) and R-2-amino-2-phenylacetic acid methyl ester hydrochloride (3.0 g, 14.3 mmol) were suspended in anhydrous dichloromethane (30 mL), HBTU (6.66 g) and DIEA (7.4 g, 57.4 mmol) were added. After the reaction mixture was stirred overnight at room temperature, water (10 mL) was added, and after separation, the organic phase was extracted twice with dichloromethane (10 mL×2), and the combined organic phase was washed once with saturated brine, washed with anhydro...

Embodiment 2

[0112] Example 2 Preparation of derivatives represented by general formula (I) (compound-2)

[0113] Preparation of (R)-4-(3-phenyl-4-(piperidin-4-ylmethylene)piperazin-1-yl)phenol (hereinafter collectively referred to as compound 2)

[0114]

[0115] Compound-2

[0116] This compound can be prepared by the following steps:

[0117]

[0118] 2.1 (R)-1-(4-(N-tert-butoxycarbonylpiperidinyl)methylene)-2-phenyl-4-(4-(tert-butyldimethylsilyloxy)phenyl) ) Preparation of piperazine (2-1)

[0119]

[0120] (R)-1-(4-(tert-Butyldimethylsilyloxy)phenyl)-3-phenylpiperazine (1-5) (100 mg) and 1-tert-butoxycarbonylpiperidine-4- Formaldehyde (69 mg) was obtained using the same experimental procedure as in step 1.5 to obtain (R)-1-(4-(N-tert-butoxycarbonylpiperidinyl)methylene)-2-phenyl-4-(4- (tert-butyldimethylsilyloxy)phenyl))piperazine (2-1) 130 mg. LC-MS (ESI): m / z (M+1) 566.4.

[0121] Phenyl-4-(piperidin-4-ylmethylene)piperazin-1-yl)phenol ( Compound 2 ) preparation

[...

Embodiment 3

[0125] The preparation of the derivative (compound-3) shown in embodiment 3 general formula (I)

[0126] Preparation of (S)-4-(4-(4-hydroxybenzyl)-3-phenylpiperazin-1-yl)phenol (hereinafter referred to as compound 3)

[0127]

[0128] Compound-3

[0129] This compound can be prepared by the following steps:

[0130]

[0131] 3.1 Preparation of (S)-2-(2-(benzyloxycarbonylamino)acetamido)-2-phenylacetic acid methyl ester (3-2)

[0132]

[0133]2-Benzyloxycarbonylaminoacetic acid (3-1) (2.98 g) and S-2-amino-2-phenylacetic acid methyl ester hydrochloride (3.0 g) were dissolved in anhydrous DMF (30 mL), and HBTU was added (6.66 g) and DIEA (7.4 g). After the reaction mixture was stirred overnight at room temperature, water (30 mL) and ethyl acetate (10 mL) were added, and after separation, the aqueous phase was extracted with ethyl acetate (10 mL X 3), and the combined organic phase was washed 3 times with brine , dried over anhydrous sodium sulfate, filtered and conc...

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Abstract

The invention provides a histone demethylase LSD1 (lysine specific demethylase 1) inhibitor. The invention relates to piperazine-containing compounds and pharmacologically acceptable salts thereof and use of the piperazine-containing compounds and pharmacologically acceptable salts thereof as the LSD1 inhibitor; the general structural formula of the piperazine-containing compounds is described in the description. The invention belongs to the field of pharmaceutical chemistry. An in-vitro LSD1 activity inhibition test proves that the piperazine-containing compounds implemented by the invention have an obvious inhibiting effect for LSD1 activity, thus being used as active ingredients for preparing LSD1 inhibitor medicines.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of piperazine-containing compounds or pharmaceutically acceptable salts thereof and their application as histone lysine demethylase LSD1 inhibitors. Background technique [0002] Abnormal expression or regulation of epigenetic proteins can lead to many diseases including cancer. For example, many pathological changes in cancer cells involve abnormal expression or regulation of one or more epigenetic proteins. By interfering with and inhibiting the epigenetic proteins involved in the disease, the process of the disease can be inhibited or even reversed, so as to achieve the purpose of alleviating or curing the disease. Now there are several anti-cancer drugs targeting epigenetic proteins on the market in the world. Epigenetic modification generally refers to DNA methylation and modification of histones. Histone modifications include acetylation, methylation...

Claims

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Application Information

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IPC IPC(8): C07D241/04C07D403/06A61K31/496A61K31/495A61P35/00C07B53/00
CPCC07B53/00C07B2200/07C07D241/04C07D403/06
Inventor 周中祥邢园园陈应忠邓承军张书祖邓洪癸李芳
Owner 福建金乐医药科技有限公司
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