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Octahydropyrrolo[3,4-c]pyrrole derivative and application method and application thereof

A technology for drugs and compounds, applied in the field of drugs, can solve problems such as safety rejection of approval, and achieve the effects of high safety, good metabolic stability, and good bioavailability

Active Publication Date: 2018-03-06
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, currently the only drug related to orexin receptors on the market is Suvorexant, an anti-insomnia drug developed by Merck of the United States, which is an orexin receptor antagonist. was rejected by the US FDA

Method used

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  • Octahydropyrrolo[3,4-c]pyrrole derivative and application method and application thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivative and application method and application thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivative and application method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Example 1: (5-(1,6-phthalazin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-methyl-2-( Synthesis of 2H-1,2,3-triazol-2-yl)phenyl)methanone

[0169]

[0170] Step 1) Synthesis of 5-chloro-1,6-naphthalene

[0171] Add 1,6-naphthyridine-5(6H)-one (3.00g, 20.53mmol) and phosphorus oxychloride (40mL) into a 100mL reaction flask, and heat the reaction to 100°C for 24 hours. The reaction was stopped, the reaction solution was cooled to room temperature, and excess phosphorus oxychloride was distilled off under reduced pressure. The remaining solid was quenched with ice saturated sodium bicarbonate solution (80 mL), and the aqueous phase was extracted with dichloromethane (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=1 / 1) to obtain the title compound (white solid, 3.08g, 91.20%).

[017...

Embodiment 2

[0194] Example 2: (5-(1,6-phthalazin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(2H-1,2 , Synthesis of 3-triazol-2-yl)phenyl)methanone

[0195]

[0196] Step 1) Synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoic acid

[0197] The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 2H-1,2,3-triazole (0.7g, 10.08mmol), 2-iodobenzoic acid (1g, 4.03mmol), carbonic acid Cesium (2.36g, 7.2mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.103g, 0.752mmol) and cuprous iodide (0.077g, 0.403mmol) on N , prepared by reaction in N-dimethylformamide (18mL), the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v)=30 / 1) to obtain the title compound (yellow solid, 0.511g, 67%).

[0198] MS(ESI,neg.ion)m / z:188.1[M-H] - ;

[0199] 1 H NMR (DMSO-d 6 ,600MHz)δ(ppm):13.06(s,1H),8.08(s,2H),7.78~7.75(m,2H),7.72~7.68(m,1H),7.60~7.57(m,1H);

[0200] 13 C NMR (DMSO-d 6 ,1...

Embodiment 3

[0208] Example 3: (5-(1,6-phthalazin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H Synthesis of -1,2,3-triazol-2-yl)phenyl)methanone

[0209]

[0210] Step 1) Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

[0211] The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 2H-1,2,3-triazole (6.9g, 100mmol), 2-fluoro-6-iodobenzoic acid (10.64g, 40mmol ), cesium carbonate (23.4g, 71.7mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (1.02g, 7.04mmol) and cuprous iodide (0.76g, 4.0mmol ) in N,N-dimethylformamide (50mL), the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v)=50 / 1) to obtain the title compound (yellow solid, 5.62g, 67.90%).

[0212] MS(ESI,pos.ion)m / z:208.10[M+H] +

[0213] 1 H NMR (DMSO-d 6 ,400MHz)δ(ppm):13.66(s,1H),8.16(s,2H),7.79(d,J=8.2Hz,1H),7.68(td,J=8.2,6.2Hz,1H),7.44( t,J=8.8Hz,1H).

[0214] Step 2) Sy...

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Abstract

The invention relates to an octahydropyrrolo[3,4-c]pyrrole derivative and an application method and application thereof. The compound and a pharmaceutical composition containing the compound are usedfor antagonizing orexin receptors. The invention also relates to a method for preparing the compound and the pharmaceutical composition and their application in treatment or prevention of diseases related to the orexin receptors.

Description

field of invention [0001] The invention belongs to the technical field of medicines, in particular to a class of substituted (octahydropyrrolo[3,4-c]pyrrol-2(1H)-yl) phenylphenone compounds, pharmaceutical compositions containing such compounds, and How they are used and what they are used for. More specifically, the compounds and pharmaceutical compositions of the present invention can be used as orexin receptor antagonists to treat, prevent or alleviate diseases related to orexin receptors. Background of the invention [0002] Orexin, also known as hypocretin and orexin, includes orexin A and orexin B (or hypocretin-1 and hypocretin-2), which are secreted by the hypothalamus Its main physiological functions are as follows: 1. Regulating food intake, orexin can significantly promote food intake, and it shows a dose-dependent response, and activates the neurons that regulate food intake; 2. Participates in the regulation of energy metabolism, orexin can significantly promot...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61K31/4375A61P25/20A61P25/24A61P25/22A61P25/00A61P15/00A61P25/30A61P25/14A61P25/04A61P25/06A61P25/08A61P29/00A61P9/00A61P3/10A61P3/00A61P37/00A61P5/00A61P9/12A61P25/18A61P25/28A61P25/16
CPCC07D519/00
Inventor 金传飞张英俊薛亚萍劳锦花聂飚许娟
Owner SUNSHINE LAKE PHARM CO LTD
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