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Cyclopropylamine spiro(hetero)cyclic compound, and pharmaceutical composition and application thereof

A technology for compounds and prodrugs, which can be used in drug combinations, preparation of amino compounds, preparation of organic compounds, etc., and can solve problems such as adverse side effects

Active Publication Date: 2016-10-26
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tranylcypromine is the active ingredient of the marketed drug Parnate, which can inhibit the above targets, but since the inhibition of MAO-A may lead to adverse side effects, it is necessary to develop highly selective cyproamine drugs

Method used

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  • Cyclopropylamine spiro(hetero)cyclic compound, and pharmaceutical composition and application thereof
  • Cyclopropylamine spiro(hetero)cyclic compound, and pharmaceutical composition and application thereof
  • Cyclopropylamine spiro(hetero)cyclic compound, and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] Embodiment 1: the synthesis of compound I-1

[0171]

[0172] Step 1: Compound II-1-1

[0173] Dissolve p-N-tert-butoxycarbonylpiperidone (76mg, 0.38mmol), intermediate II-1 (60mg, 0.38mmol) and glacial acetic acid (23mg, 0.38mmol) in 1,2-dichloroethane (5mL ), stirred at room temperature for 1 hour, cooled in an ice bath, added sodium acetate borohydride (145mg, 0.68mmol), stirred at room temperature overnight, the reaction solution was quenched with dichloromethane, and the organic phase was washed successively with 1M citric acid solution and saturated brine , the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol=20 / 1) to obtain compound II-1-1 (20 mg, yield: 15%) as an oily liquid.

[0174] m / z: [M+H] + 343

[0175] Step 2: Compound I-1

[0176] Compound II-1-1 (20mg, 0.06mmol) and 2,6-lutidine (13mg, 0.12mmol) were dissolved in anhydrous dichloromethane (1mL), and trifluoromethanesulfon was added dr...

Embodiment 2

[0179] Example 2: Using the synthesis method of compound I-1, and corresponding aldehydes or ketones to synthesize stereoisomer mixtures I-2 to I-4:

[0180]

Embodiment 3

[0181] Embodiment 3: the synthesis of compound 1-5

[0182]

[0183] Dissolve 1-benzyl-4-piperidinecarbaldehyde (64 mg, 0.31 mmol), intermediate II-1 (50 mg, 0.31 mmol) and 2 drops of glacial acetic acid in 1,2-dichloroethane (1 mL), room temperature Stir for 1 hour, cool in an ice bath, add sodium acetate borohydride (197mg, 0.93mmol), stir at room temperature for 16 hours, dilute the reaction solution with dichloromethane (20mL), use saturated sodium bicarbonate solution (10mLx2), saturated It was washed with brine, dried over anhydrous sodium sulfate, concentrated by filtration and purified by silica gel column chromatography (dichloromethane / methanol=20) to obtain compound I-5 (25 mg, yield: 22%) as a yellow oil.

[0184] m / z: [M+H] + 347

[0185] 1 HNMR (DMSO-d 6 , 400Hz): δ7.14-7.33(m, 8H), 7.04-7.14(m, 1H), 3.44(s, 2H), 2.23-2.93(m, 5H), 1.45-2.57(m, 12H), 1.06 -1.17 (m, 2H).

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PUM

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Abstract

The invention relates to a preparation method for a cyclopropylamine spiro(hetero)cyclic compound and a composition containing the same, and application of the compound and the composition as an inhibitor for human lysine-specific demethylase (LSD1). The inhibitor is the cyclopropylamine spiro(hetero)cyclic compound as shown in a formula (I) which is described in the specification, or a pharmaceutically acceptable salt, predrug, solvate, polymorphic crystal or stable isotope derivative thereof. The compound can be used for treating or preventing diseases related to human lysine-specific demethylase, e.g., cancers and nerve diseases.

Description

technical field [0001] The invention relates to a cyclopropylamine spiro (hetero) ring compound, its isomer, prodrug or pharmaceutically acceptable salt, stable isotope derivative, its pharmaceutical composition, preparation method and application. Background technique [0002] Human lysine specific demethylasel (LSD1) is a member of the amine oxidase family. With the participation of flavin adenine dinucleotide (FAD), LSD1 can specifically remove histone H3 Dimethyl and monomethyl modifications on fourth (H3K4) and ninth (H3K9) lysine residues. LSD1 can also remove methylation modifications on some other non-histone substrates, such as p53 and DNMT1. LSD1 has a variety of biological functions, mainly including promoting tumor proliferation, inhibiting energy metabolism, promoting fat synthesis, inhibiting lipolysis and regulating cell differentiation. Therefore, LSD1 is a potential drug target for the prevention and treatment of various diseases. [0003] LSD1 is overexp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/42C07C209/62C07C209/28C07C255/58C07C253/30C07D311/96C07D221/20C07D211/26C07D211/58C07D405/12C07D401/12C07D231/12A61K31/135A61K31/352A61K31/438A61K31/4465A61K31/4468A61K31/453A61K31/454A61K31/415A61K31/277A61K31/4545A61P25/24A61P25/18A61P25/28A61P25/14A61P25/16A61P21/00A61P35/00A61P35/02
Inventor 孔诺尔曼祥龙高大新
Owner SHANGHAI DE NOVO PHARMA
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