2-Substituted oxy-5-methylsulfonyl phenylpiperazinamide analogues and their preparation method and use

A kind of arylpiperazinamide and analog technology, applied in the field of 2-substituted oxy-5-methylsulfonyl phenylpiperazinamide analog and preparation thereof, can solve negative symptoms and cognitive symptoms without improvement And other issues

Active Publication Date: 2021-03-26
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs did not improve negative and cognitive symptoms (Sharma, T.; 1999, Br. J. Psychiatry, 1999, 174, 44-51)

Method used

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  • 2-Substituted oxy-5-methylsulfonyl phenylpiperazinamide analogues and their preparation method and use
  • 2-Substituted oxy-5-methylsulfonyl phenylpiperazinamide analogues and their preparation method and use
  • 2-Substituted oxy-5-methylsulfonyl phenylpiperazinamide analogues and their preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] 4-(4-(2-((1-methylcyclopropyl)methoxy)-5-(methylsulfonyl)benzoyl)piperazin-1-yl)benzonitrile

[0158]

[0159] The first step: 5-(chlorosulfonyl)-2-fluorobenzoic acid

[0160] Take a 250mL three-necked flask, add chlorosulfonic acid (70mL, 1.06mol) and a stirrer, cool to 0°C, add 2-fluorobenzoic acid (25g, 179mmol) in batches, after the addition is completed, gradually rise to room temperature and react for 1h, 70 Stir overnight at ℃, cool to room temperature, add 500 mL of ice water dropwise, precipitate a solid, filter, wash the solid with water, and dry to obtain a white solid, which is directly carried out to the next reaction.

[0161] The second step: 2-fluoro-5-sulfinic acid

[0162] Dissolve sodium sulfite (125g, 0.99mol) in 400mL water, add 5-(chlorosulfonyl)-2-fluorobenzoic acid prepared in the first step in batches, stir at room temperature for 2h, cool to 0°C, add 20% sulfuric acid dropwise (150 mL), adjust the pH to 2, distill off the water, add 600 mL...

Embodiment 2

[0174] {4-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}{2-[(1-methylcyclopropyl)methoxy]-5-( Methylsulfonyl)phenyl}methanone

[0175]

[0176] The first step: 2-[(1-methylcyclopropyl)methoxy]-5-(methylsulfonyl)benzoic acid

[0177] Dissolve 2-fluoro-5-(methylsulfonyl)benzoic acid (436mg, 2mmol) in dimethylacetamide (5mL), add (1-methylcyclopropyl)methanol (344mg, 4mmol) and anhydrous Potassium carbonate (553 mg, 4 mmol). Rise to 150°C to react overnight. Evaporate the solvent, add water to dissolve, then adjust the pH value to about 2 with 1N hydrochloric acid, a white solid precipitates, filter the solid, and wash with water three times to obtain 2-[(1-methylcyclopropyl)methoxy]- 5-(methylsulfonyl)benzoic acid (460mg, white solid), the yield was 81%.

[0178] The second step: {4-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}{2-[(1-methylcyclopropyl)methoxy] -5-(methylsulfonyl)phenyl}methanone

[0179] 2-[(1-Methylcyclopropyl)methoxy]-5-(methyls...

Embodiment 3

[0182] (4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)(2-((1-methylcyclopropyl)methoxy)-5-(methylsulfonyl)phenyl) ketone

[0183]

[0184] Take a 50mL single-necked bottle, add 2-((1-methylcyclopropyl)methoxy)-5-(methylsulfonyl)benzoic acid (81mg, 0.36mmol), 1-(2-fluoro-4-nitro phenyl)piperazine (80mg, 0.3mmol), HATU (171mg, 0.45mmol), TEA (0.16mL, 1.08mmol), DMF (10mL), react overnight at room temperature, add saturated sodium chloride (20mL), and wash with acetic acid Ethyl ester (20mL*3) was extracted, the organic phase was dried with anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product, which was prepared by reverse phase to obtain 85 mg of a pure product, yield: 48%.

[0185] 1 H NMR (400MHz, CDCl 3 )δ8.02(dd,J=8.9,1.8Hz,1H),7.99–7.91(m,2H),7.89(d,J=2.3Hz,1H),7.00(d,J=8.8Hz,1H), 6.94(t,J=8.7Hz,1H),4.10–3.92(m,3H),3.80(d,J=9.1Hz,1H),3.62–3.24(m,6H),3.05(s,3H),1.21 (s, 3H), 0.49 (ddd, J = 16.0, 11.5, 6.0Hz, 4H).

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Abstract

The invention discloses 2-substituted-phenyl-oxy-5-methylsulfonyl piperazine acidamide analogue and a preparation method and application thereof, and particularly, relates to 2-substituted-phenyl-oxy-5-methylsulfonyl piperazine acidamide analogue with a formula (I) compound and a preparation method and application thereof, wherein substitutions in the formula (I) compound are defined as in the description. This serial compound can inhibit the activity of glycine transport protein-1 (GlyT1), is useful in treating related diseases in central nerve and psychological fields, for example, schizophrenia (including positive symptoms, negative symptoms and cognitive symptoms), senile dementia, Parkinson's disease and other related psychological diseases, is widely applicable to the drugs for preventing and treating central nerve and psychological diseases, and is expected to be developed into new-generation GlyT1 inhibitors.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a 2-substituted oxy-5-thiamphenicol phenylpiperazine amide analogue and a preparation method and application thereof. Background technique [0002] Schizophrenia is a progressive and destructive mental illness. According to symptoms, schizophrenia is usually divided into three types of symptoms in the world: positive symptoms, negative symptoms and cognitive symptoms. Yang and sexual symptoms are manifested as delusions, hallucinations, strange behaviors, and thinking disorders; negative symptoms are manifested as flat emotions, loss of interest, decreased willpower, and reduced speech; cognitive symptoms are manifested as long-term memory, operational memory, and abstraction. and planning, and speech comprehension and creativity (Lewis, D.A.; Lieberman J.A. Neuron, 2000, 28, 325-33). For decades, the scientific community has focused on the "dopamine hypothesis" that schizo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/192C07D213/74C07D277/42C07D261/20C07D307/88C07D215/46C07D271/07C07D277/82C07D277/56C07D275/04A61K31/495A61K31/496A61P25/18A61P25/28A61P25/16A61P25/00
CPCC07D213/74C07D215/46C07D261/20C07D271/07C07D275/04C07D277/42C07D277/56C07D277/82C07D295/192C07D307/88
Inventor 廖建春喻红平徐耀昌陈江华王少宝修文华刘昭敏
Owner SHANGHAI HANSOH BIOMEDICAL
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