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2-Substituted-oxy-5-methylsulfonyl pyridine piperazine acidamide analogue and preparation method and application thereof

A technology of thiamphenicol pyridine piperazine amide and analogues, applied in the field of 2-substituted oxy-5-thiamphenicol pyridine piperazinamide analogues and their preparation, capable of solving negative symptoms and no improvement in cognitive symptoms And other issues

Inactive Publication Date: 2016-06-29
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 pyridine piperazine acidamide analogue and preparation method and application thereof
  • 2-Substituted-oxy-5-methylsulfonyl pyridine piperazine acidamide analogue and preparation method and application thereof
  • 2-Substituted-oxy-5-methylsulfonyl pyridine piperazine acidamide analogue and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0093] 1. Preparation of important intermediates

[0094] 1. Preparation of intermediate 1: 1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazine

[0095]

[0096] 2,3-5-Trifluoromethylpyridine (15.0g, 0.08mmoL) and potassium carbonate (33.9g, 0.24g) were dissolved in tetrahydrofuran, piperazine (35.2g, 0.4mmoL) was added in batches under an ice-water bath, and then Stir at room temperature for 1 hour, then extract with 40 mL of toluene, wash three times with water, dry the organic phase over sodium sulfate, filter and evaporate the solvent to obtain 1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl ) piperazine (10 g).

[0097] 2. Preparation of intermediate 2: 1-(2-fluoro-4-(trifluoromethyl)phenyl)piperazine

[0098]

[0099] Weigh 2-fluoro-4-trifluoromethylbromobenzene (243mg, 1.0mmol), piperazine (95mg, 1.1mmol), bis(tri-tert-butylphosphine)palladium (51mg, 0.10mmol) and cesium carbonate (489mg , 1.5mmol), added to 5mL of toluene, pumped and ventilated, nitrogen protec...

Embodiment 1

[0293] (4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)(5-(methylsulfonyl)-2-((1,1,1-trifluoro Propan-2-yl)oxo)pyridin-3-yl)methanone

[0294]

[0295] (5-bromo-2-((1,1,1-trifluoropropan-2-yl)oxo)pyridin-3-yl)(4-(3-fluoro-5-(trifluoromethyl)pyridine- 2-yl)piperazin-1-yl)methanone (150mg, 0.28mmol), sodium methanesulfinate (198mg, 1.65mmol), cuprous iodide (26mg, 0.14mmol) and sodium proline (38mg , 0.28mmol), dissolved in 3mL dimethyl sulfoxide, pumped, nitrogen protection. Heat at 120°C to react overnight, cool to room temperature after the reaction is complete, and add water to quench. The reaction mixture was separated by reverse-phase column chromatography to obtain a white solid (4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)(5-(methylsulfonyl) -2-((1,1,1-trifluoropropan-2-yl)oxo)pyridin-3-yl)methanone (60 mg, 40%).

[0296] LC-MS:t R =4.39min, [M+H] + =545.0;

[0297] 1 HNMR (400MHz, CDCl 3 )δ8.69(d, J=2.4Hz, 1H), 8.19(d, J=0.9Hz, 1H)...

Embodiment 2

[0300] (S)-(4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)(5-(methylsulfonyl)-2-((1,1, 1-trifluoropropan-2-yl)oxo)pyridin-3-yl)methanone

[0301]

[0302] The preparation method refers to Example 1.

[0303] LC-MS:t R =3.03min, [M+H] + =545.0;

[0304] 1 HNMR (400MHz, CDCl 3 )δ8.69(d,J=2.4Hz,1H),8.18(s,1H),8.13(s,1H),7.37(dd,J=13.0,1.7Hz,1H),5.93(brs,1H), 3.99–3.43(m,6H),3.29(brs,2H),3.06(s,3H),1.47(brs,3H);

[0305] 19 FNMR (376MHz, CDCl 3 ) δ -61.23(s), -78.01(s), -127.72(d, J=11.7Hz).

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Abstract

The invention discloses 2-substituted-oxy-5-methylsulfonyl pyridine piperazine acidamide analogue and a preparation method and application thereof, and particularly, relates to 2-substituted-oxy-5-methylsulfonyl pyridine 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 pyridine piperazine 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, as well as speech comprehension and creativity (Lewis, D.A.; LiebermanJ.A. Neuron, 2000, 28, 325-33). For decades, the scientific community has focused on the "dopamine hypothesis" th...

Claims

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Application Information

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IPC IPC(8): C07D213/82A61P25/00A61P25/18A61P25/28A61P25/16A61P25/32A61P25/08A61P25/04
CPCC07D213/82
Inventor 杨飞张秀春孙兴义危明松王春娟仝朝龙李成海包如迪喻红平徐耀昌
Owner SHANGHAI HANSOH BIOMEDICAL
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