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Octahydropyrrolo[3,4-c]pyrrole derivatives and methods and uses thereof

A use, n-c technology, applied in the field of medicine, can solve problems such as safety refusal

Active Publication Date: 2021-11-12
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 derivatives and methods and uses thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivatives and methods and uses thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivatives and methods and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] 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

[0171]

[0172] Step 1) Synthesis of 5-chloro-1,6-naphthalene

[0173] 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, 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%).

[0174] M...

Embodiment 2

[0196] 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

[0197]

[0198] Step 1) Synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoic acid

[0199] 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%).

[0200] MS(ESI,neg.ion)m / z:188.1[M-H] - ;

[0201] 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);

[0202] 13 C NMR (DMSO-d 6 ,1...

Embodiment 3

[0210] 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

[0211]

[0212] Step 1) Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

[0213] 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%).

[0214] MS(ESI,pos.ion)m / z:208.10[M+H] +

[0215] 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).

[0216] Step 2) Sy...

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Abstract

The present invention relates to octahydropyrrolo[3,4-c]pyrrole derivatives and methods and uses thereof. The compounds of the present invention and pharmaceutical compositions comprising the compounds are used to antagonize orexin receptors. The present invention also relates to methods of preparing such compounds and pharmaceutical compositions, and their use in the treatment or prevention of diseases associated with orexin receptors.

Description

[0001] field of invention [0002] 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. [0003] Background of the invention [0004] 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 signi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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