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

A technology of drugs and compounds, applied in the field of octahydropyrrolo[3,4-c]pyrrole derivatives, which can solve the problems of safety refusal, achieve high safety, good efficacy, and promote side effects

Active Publication Date: 2019-07-09
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 thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivative and application thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] Example 1 (5-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-methyl) Synthesis of base-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0176]

[0177] Step 1) Synthesis of 5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester

[0178]

[0179] 5-Bromo-2-chloropyrimidine (2.902 g, 15.00 mmol), hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (2.123 g, 10.00 mmol), carbonic acid Potassium (2.792 g, 20.00 mmol) and acetonitrile (50 mL) were added to a 250 mL reaction flask, and the reaction was refluxed at 90° C. for 8 hours. TLC detected the completion of the reaction and stopped the reaction. Evaporated to dryness and purified by silica gel column (petroleum ether / ethyl acetate (v / v)=5 / 1) to give the title compound as a white solid (2.91 g, 78.8%).

[0180] MS(ESI,pos.ion)m / z:314.20[M+H-56] + ;

[0181] 1 HNMR (400MHz, CDCl 3 )δ(ppm): 8.29(s, 2H), 3.77(d, J=5.9Hz, 2H), 3.63(d...

Embodiment 2

[0198] Example 2 (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)hexahydro Synthesis of pyrrolo[3,4-c]pyrrole 2(1H)-yl)methanone

[0199]

[0200] 2-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole hydrochloride (330 mg, 0.96 mmol) (refer to the present application, carried out Example 1, the synthesis from step 1) to step 3)) and dichloromethane (15mL) were added to a 50mL two-necked flask, and after stirring at 0°C for 10min, triethylamine (0.54mL, 3.85mmol) was added, and stirring was slowly added dropwise. 2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (239 mg, 1.15 mmol) dissolved in dichloromethane (5 mL) was added (refer to patent CN105949203 A, Example 2, Step 1) To the synthesis of step 2)), the temperature is controlled below 5 °C, the dropwise addition is completed, and the reaction is continued at 0 °C-5 °C for 2 hours, and then at room temperature for 12 hours. TLC detected the completion of the reaction, stopped the r...

Embodiment 3

[0204] Example 3 (5-(5-(2,2-Difluoroethoxy)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro Synthesis of -6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0205]

[0206]2-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole hydrochloride (350 mg, 1.02 mmol) (refer to this application, carried out Example 1, the synthesis from step 1) to step 3)) and dichloromethane (15mL) were added into a 50mL two-necked flask, and after stirring at 0°C for 10min, triethylamine (0.57mL, 4.08mmol) was added, and stirring was slowly added dropwise. Add 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl chloride (276mg, 1.22mmol) dissolved in dichloromethane (5mL) (refer to patent CN105949203 A, Example 3 , the synthesis from step 1) to step 2), the temperature is controlled below 5°C, the dropwise addition is completed, and the reaction is continued at 0°C-5°C for 2 hours, and then at room temperature for 12 hours. The reaction was stopped, the solvent was evaporated to d...

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Abstract

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

Description

[0001] Field of Invention [0002] The present invention belongs to the technical field of medicine, and specifically relates to a class of octahydropyrrolo[3,4-c]pyrrole derivatives, pharmaceutical compositions containing such compounds, and their use methods and uses. More specifically, the compounds and pharmaceutical compositions of the present invention can be used as orexin receptor antagonists for the treatment, prevention or alleviation of orexin receptor-related diseases. [0003] Background of the Invention [0004] Orexin, also known as hypocretin, orexin, which includes orexin A and orexin B (or hypocretin-1 and hypocretin-2), is a hormone secreted by the hypothalamus. Its main physiological functions are: 1. Regulating food intake, orexin can significantly promote food intake in a dose-dependent manner, and activate neurons that regulate food intake; 2. Participate in the regulation of energy metabolism, orexin can significantly promote food intake Increase metabo...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/506A61P25/20A61P25/22A61P25/24A61P25/18A61P15/00A61P25/28A61P25/30A61P25/16A61P25/14A61P9/12A61P5/00A61P37/00A61P3/00A61P3/10A61P9/00A61P29/00A61P25/08A61P25/06A61P1/00
CPCC07D487/04
Inventor 金传飞许腾飞薛亚萍郭正江
Owner SUNSHINE LAKE PHARM CO LTD
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