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

A technology of drugs and compounds, applied in the field of octahydropyrrolo[3,4-c]pyrrole derivatives, can solve problems such as safety refusal to approve

Active Publication Date: 2022-04-26
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 uses thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] Example 1 (5-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-methyl Synthesis of 2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0175]

[0176] Step 1) Synthesis of 5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0177]

[0178] 5-Bromo-2-chloropyrimidine (2.902g, 15.00mmol), hexahydropyrrolo[3,4-c]pyrrole-2(1H)-tert-butyl carboxylate (2.123g, 10.00mmol), carbonic acid Potassium (2.792g, 20.00mmol) and acetonitrile (50mL) were added into a 250mL reaction flask, and the mixture was refluxed at 90°C for 8 hours. TLC detects that the reaction is complete, and the reaction is stopped. Evaporated to dryness and purified by silica gel column (petroleum ether / ethyl acetate (v / v)=5 / 1) to obtain the title compound as a white solid (2.91 g, 78.8%).

[0179] MS(ESI,pos.ion)m / z:314.20[M+H-56] + ;

[0180] 1 HNMR (400MHz, CDCl 3 )δ (ppm): 8.29 (s, 2H), 3.77 (d, J = 5.9Hz, 2H), 3.63 (d, J = 5...

Embodiment 2

[0197] 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

[0198]

[0199] 2-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole hydrochloride (330mg, 0.96mmol) (refer to this application, implement Example 1, Synthesis of Step 1) to Step 3)) and dichloromethane (15mL) into a 50mL two-neck flask, stirred at 0°C for 10min, then added triethylamine (0.54mL, 3.85mmol), stirred slowly Add 2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (239 mg, 1.15 mmol) dissolved in dichloromethane (5 mL) (refer to patent CN105949203 A, Example 2, step 1) To the synthesis of step 2), the temperature was controlled below 5°C, after the dropwise addition was completed, the reaction was continued at 0°C-5°C for 2 hours, and then at room temperature for 12 hours. The completion of the reaction was detected by TLC, the reaction was stopped, the solvent was evaporated to dryness, purified ...

Embodiment 3

[0203] 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

[0204]

[0205]2-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole hydrochloride (350mg, 1.02mmol) (refer to this application, implement Example 1, Synthesis of Step 1) to Step 3)) and dichloromethane (15mL) into a 50mL two-necked flask, stirred at 0°C for 10min, then added triethylamine (0.57mL, 4.08mmol), stirred slowly Add 2-fluoro-6-(2H-1,2,3-triazol-2-yl) benzoyl chloride (276 mg, 1.22 mmol) dissolved in dichloromethane (5 mL) (refer to patent CN105949203 A, Example 3 , step 1) to step 2) synthesis), the temperature was controlled below 5°C, after the dropwise addition was completed, the reaction was 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 dryness, purified by silica gel column (petroleum ether / ...

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Abstract

The present invention relates to octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof. The compound of the present invention and the pharmaceutical composition comprising the compound are used for antagonizing orexin receptors. The present invention also relates to methods for preparing these compounds and pharmaceutical compositions, and their use in treating or preventing diseases related to orexin receptors.

Description

[0001] field of invention [0002] The invention belongs to the technical field of medicines, and specifically relates to a class of octahydropyrrolo[3,4-c]pyrrole derivatives, a pharmaceutical composition containing such compounds, and their use methods and purposes. 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 significantly promote Increase metabolic ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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