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

A compound, -NH2 technology, applied in the field of medicine, can solve the problem of safety refusal to approve, and achieve the effect of high safety, low toxicity and side effects, and good bioavailability

Active Publication Date: 2018-07-20
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 use thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivatives and use thereof
  • Octahydropyrrolo[3,4-c]pyrrole derivatives and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0193] Example 1: 6-(5-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole Synthesis of -2(1H)-yl)pyridine-2(1H)-one

[0194]

[0195] Step 1) Synthesis of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

[0196] 1,2,3-Triazole (3.45g, 50mmol), 2-iodo-5-methylbenzoic acid (5.24g, 20mmol), cesium carbonate (11.72g, 36mmol), trans-N,N' -Dimethyl-1,2-cyclohexanediamine (0.51g, 3.6mmol), cuprous iodide (0.38g, 2mmol), N,N-dimethylformamide (30mL) were added to 100mL single-mouth circle in turn In the bottom flask, the temperature was gradually raised to 100°C for 4 hours under the protection of nitrogen. The reaction was stopped, cooled, diluted with tap water and extracted with ethyl acetate (200 mL×2). The aqueous layer was acidified with concentrated hydrochloric acid (pH=1~2) and then extracted with ethyl acetate (200mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduc...

Embodiment 2

[0214] Example 2: 6-(5-(2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H) -Yl)pyridine-2(1H)-one synthesis

[0215]

[0216] Step 1) Synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoic acid

[0217] The title compound in this step was prepared by referring to the method described in step 1 of Example 1, namely 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 -Dimethylformamide (18mL) prepared by reaction, 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%) ).

[0218] MS(ESI,neg.ion)m / z:188.1[M-H] - ;

[0219] 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).

[0220] Step 2) Synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoyl chlori...

Embodiment 3

[0235] Example 3: 6-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole- Synthesis of 2(1H)-yl)pyridine-2(1H)-one

[0236]

[0237] Step 1) Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

[0238] The title compound in this step was prepared by referring to the method described in step 1 of Example 1, namely 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), cuprous iodide (0.76g, 4.0mmol) in Prepared by reaction in N,N-dimethylformamide (50mL), the crude product is 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%).

[0239] MS(ESI,pos.ion)m / z:208.10[M+H] + ;

[0240] 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).

[0241] Step 2) Synthesis ...

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Abstract

The invention relates to octahydropyrrolo[3,4-c]pyrrole derivatives and a use thereof. The above compounds and a medicinal composition containing the compounds are used for suppressing an orexin receptor. The invention also relates to a method for preparing the compounds and the medicinal composition, and the use of the compounds and the medicinal composition in the treatment or prevention of orexin receptor related diseases.

Description

Invention field [0001] The 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 to treat, prevent or alleviate orexin receptor-related diseases. Background of the invention [0002] Orexin (orexin) is also called hypothalamic secretion, orexin, which includes orexin A and orexin B (or hypothalamic secretin-1 and hypothalamic secretin-2), which is a secretion from the hypothalamus The main physiological functions of the neuropeptides are as follows: 1. Regulating food intake, orexin can significantly promote eating, with a dose-dependent response, and activates the neurons that regulate eating; 2. Participating in the regulation of energy metabolism, orexin can be significant Incre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4439A61K31/517A61P25/28A61P25/18A61P25/24A61P25/22A61P25/30A61P25/08A61P25/14A61P25/16A61P25/06A61P25/04A61P25/20A61P25/00A61P29/00A61P9/12A61P3/10A61P3/00A61P9/00A61P37/02A61P5/00
CPCC07D487/04
Inventor 金传飞劳锦花张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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