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

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

Active Publication Date: 2022-01-11
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

[0190] Example 1 2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2( Synthesis of 1H)-yl)-4-methylthiazole-5-carboxamide

[0191]

[0192] 2-Bromo-4-methylthiazole-5-carboxamide (295mg, 1.33mmol), (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(hexa Hydrogen pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride (500mg, 1.34mmol) (reference patent CN105949203 A, synthesis of Example 3), sodium carbonate (0.569g, 5.34 mmol) and acetonitrile (15 mL) were added into a 100 mL reaction flask, and reacted at 80° C. under reflux for 12 hours. The completion of the reaction was monitored by TLC, the reaction was stopped, cooled to room temperature, and spin-dried. Purification by silica gel column (dichloromethane / methanol (v / v)=40 / 1) gave the title compound as a yellow solid (510 mg, yield: 86.5%).

[0193] MS(ESI,pos.ion)m / z:442.50[M+H] + ;

[0194] 1 H NMR (400MHz, CDCl 3 )δ(ppm): 7.90–7.73(m,3H), 7.50(dt, J=14.3,7.3Hz,1H), 7.17(t,J=8.5Hz,1H), 5.67...

Embodiment 2

[0196] Example 2 2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2( Synthesis of 1H)-yl)-4-methylthiazole-5-carbonitrile

[0197]

[0198] 2-Bromo-4-methylthiazole-5-carbonitrile (325mg, 1.60mmol), (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)( Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride (600mg, 1.60mmol) (refer to patent CN 105949203A, synthesis of Example 3), sodium carbonate (0.683g, 6.41 mmol) and acetonitrile (15 mL) were added into a 100 mL reaction flask, and reacted at 80° C. under reflux for 12 hours. The reaction was monitored by TLC, the reaction was stopped, cooled to room temperature, and spin-dried. Purification by silica gel column (dichloromethane / methanol (v / v)=50 / 1) gave the title compound as a white solid (623 mg, yield: 91.7%).

[0199] MS(ESI,pos.ion)m / z:424.05[M+H] + ;

[0200] 1 H NMR (400MHz, CDCl 3 )δ (ppm): 7.90–7.75 (m, 3H), 7.51 (dd, J = 14.3, 8.2Hz, 1H), 7.17 (td, J = 8.5, 2.7Hz, 1H), 3.96 (d...

Embodiment 3

[0202] Example 3 4-methyl-2-(5-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4- c] Synthesis of pyrrole-2 (1H) base) thiazole-5-carboxylic acid ethyl ester

[0203]

[0204] 2-Bromo-4-methylthiazole-5-carboxylic acid ethyl ester (220mg, 0.88mmol), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-methyl Base-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride (293mg, 0.88mmol) (refer to patent CN 105949203 A, the synthesis of Example 1), triethyl Amine (445mg, 4.4mmol) and N,N-dimethylformamide (8mL) were added into a 50mL reaction flask and reacted at 60°C for 12 hours. TLC detects that the reaction is complete, and the reaction is stopped. Water (50 mL) was added, extracted with dichloromethane (50 mL*2), the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. Purified by silica gel column (dichloromethane / methanol (v / v)=50 / 1), concentrated and dried to obtain the title compound as a tan solid (350 mg, ...

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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): C07D487/04A61K31/427A61P25/24A61P25/22A61P25/18A61P25/28A61P25/16A61P25/14A61P25/06A61P25/30A61P29/00A61P25/08A61P37/00A61P9/12A61P9/00A61P5/00A61P3/10A61P3/00A61P1/00
CPCC07D487/04
Inventor 金传飞许腾飞张英俊薛亚萍
Owner SUNSHINE LAKE PHARM CO LTD
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