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

A technology of drugs and compounds, applied in the field of drugs, can solve problems such as safety refusal to achieve high safety, improved tolerance, and good antagonistic activity

Active Publication Date: 2018-07-13
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

[0178] Example 1: 6-fluoro-2-(5-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4 -c] Synthesis of pyrrol-2(1H)-yl)quinazolin-4(3H)-one

[0179]

[0180] Step 1) Synthesis of 6-fluoroquinazoline-2,4(1H,3H)-dione

[0181] Urea (29.0g, 482.9mmol) and 2-amino-5-fluorobenzoic acid (5.0g, 32.2mmol) were successively added into a 200mL airtight sealed tube, and the temperature was gradually raised to 160°C under vigorous stirring, and then heated to After 4 hours at 180°C, gradually cool to room temperature, add tap water (150mL) to the reaction solution, stir at room temperature for 1 hour, then filter with suction, wash the filter residue with a large amount of tap water until the filtrate is colorless, then wash the filter residue with acetone (150mL) , washed with methanol (70 mL), and the residue was dried to obtain the title compound (brick red solid, 5.041 g, 86.8%).

[0182] MS(ESI,neg.ion)m / z:179.1[M-H] - ;

[0183] 1 H NMR (d 6 -DMSO,600MHz)δ(ppm):...

Embodiment 2

[0211] Example 2: 6-fluoro-2-(5-(2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole- Synthesis of 2(1H)-yl)quinazolin-4(3H)-one

[0212]

[0213] Step 1) Synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoic acid

[0214] The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 1,2,3-triazole (0.7g, 10.08mmol), 2-iodobenzoic acid (1g, 4.03mmol), cesium carbonate ( 2.36g, 7.2mmol), trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.103g, 0.752mmol), cuprous iodide (0.077g, 0.403mmol) in N,N -Prepared by reaction in 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% ).

[0215] MS(ESI,neg.ion)m / z:188.1[M-H] - ;

[0216] 1 H NMR (DMSO-d 6 ,600MHz)δ(ppm):13.06(w,1H),8.08(s,2H),7.78~7.75(m,2H),7.72~7.68(m,1H),7.60~7.57(m,1H).

[0217] 13 C NMR (DMSO-d 6 ,151MHz)...

Embodiment 3

[0232] Example 3: 6-fluoro-2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4- c] Synthesis of pyrrol-2(1H)-yl)quinazol-4(3H)-one

[0233]

[0234] Step 1) Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

[0235] The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 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 Prepared by reacting 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%).

[0236] MS(ESI,pos.ion)m / z:208.10[M+H] + ;

[0237] 1 H NMR (d 6 -DMSO,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). ...

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Abstract

The invention relates to an ctahydropyrrole[3, 4-c]pyrrole derivative and a using method and application thereof. A compound and a drug composition containing the same are used for resisting orexin receptors. The invention further relates to methods of preparing the compound and the drug composition and application of the compound and the drug composition in treating or preventing 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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/517A61P25/20A61P25/22A61P25/24A61P15/00A61P25/18A61P25/06A61P25/04A61P29/00A61P25/28A61P25/30A61P25/16A61P15/14A61P1/00A61P25/08A61P9/00A61P3/10A61P3/00A61P37/02A61P9/12A61P5/00
CPCC07D487/04
Inventor 金传飞许娟钟文和张英俊刘琦
Owner SUNSHINE LAKE PHARM CO LTD
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